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Bioinformatics
Methods and Applications
Bioinformatics
Methods and Applications

Edited by
Dev Bukhsh Singh
Department of Biotechnology, Institute of Biosciences and Biotechnology,
Chhatrapati Shahu Ji Maharaj University, Kanpur, India

Rajesh Kumar Pathak

School of Agricultural Biotechnology, Punjab Agricultural University,
Ludhiana, India
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Contents

List of contributors xvii 2. Biological databases and their

Preface xxi application 17
Parva Kumar Sharma and Inderjit Singh Yadav
1. Introduction to basics of
bioinformatics 1 2.1 Introduction 17
2.1.1 Relational databases 17
Rajesh Kumar Pathak, Dev Bukhsh Singh
2.1.2 Object-oriented databases 17
and Rahul Singh
2.2 Sequence databases 19
1.1 Introduction 1 2.2.1 GenBank 19
1.1.1 Concept behind bioinformatics, 2.2.2 European Nucleotide Archive 19
in silico biology, and 2.2.3 DNA Database of Japan 20
computational biology 3 2.2.4 GenPept 20
1.1.2 Scientific discipline and support 2.2.5 Protein information resources 20
systems for bioinformatics 5 2.3 Composite database 21
1.1.3 Needs of bioinformatics 5 2.3.1 Universal Protein Resource (UniProt) 21
1.2 Historical background of bioinformatics 5 2.3.2 Nonredundant database 22
1.3 Aim of bioinformatics 7 2.4 Secondary database 22
2.4.1 PROSITE 22
1.4 The recent development in the field of
2.4.2 PRINTS 22
bioinformatics 7
2.4.3 Pfam 23
1.5 Challenges in bioinformatics 8
2.4.4 InterPro 23
1.6 Application of bioinformatics 8
2.5 Structural databases 23
1.6.1 Sequence analysis 8
2.5.1 Research collaboratory for structural
1.6.2 Phylogenetic analysis 8
bioinformatics protein data bank 23
1.6.3 Prediction of protein secondary
2.5.2 SCOP 24
structure 9
2.5.3 CATH/Gene3D 24
1.6.4 Protein 3D structure prediction 9
2.6 Specialized database 24
1.6.5 Evaluation and validation of
2.6.1 Clustering databases 24
predicted protein model 10
2.6.2 Bibliographic databases 26
1.6.6 Discovery and designing of small
2.6.3 Expression databases 26
molecules leading to drugs/
2.6.4 Taxonomy databases 26
agrochemical development 10
2.6.5 Interaction databases 26
1.6.7 Next-generation sequencing data 2.6.6 Pathway databases 27
analysis 10 2.6.7 Enzyme databases 27
1.6.8 SNP and SSR identification 10 2.6.8 microRNA database 27
1.6.9 Pharmacogenomics 10 2.6.9 Small molecule database 27
1.6.10 Metabolomics and metabolic 2.6.10 Vaccine design database 28
flux analysis 11 2.7 Database searching and annotation 28
1.6.11 Systems biology and omics 2.7.1 Entrez 28
data integration 11 2.7.2 The sequence retrieval system 28
1.7 Future perspective 11 2.7.3 Annotation 28
1.8 Conclusion 11 2.8 Conclusions 29
Conflict of interest 12 Conflict of interest 29
References 12 References 29

v
vi Contents

3. Biological sequence analysis 33 4.3 Data preprocessing 52

4.3.1 Quality control of raw
Samvedna Shukla, Bhawana Mishra, sequencing data 52
Himanshu Avashthi and Muktesh Chandra 4.3.2 Trimming and filtering of raw reads 52
3.1 Introduction 33 4.4 Genome assembly approaches: types of
3.2 Sequence alignments: determining assembly 52
similarity and deducing homology 34 4.4.1 De novo assembly approach 52
3.2.1 Why construct sequence alignment? 34 4.4.2 Reference-based
3.2.2 Similarity of sequences 34 assembly approach 54
3.2.3 Homology of sequences 35 4.4.3 Hybrid assembly approach 54
3.2.4 Global sequence alignment 35 4.4.4 Meta-assembly approach 54
3.2.5 Local sequence alignment 35 4.5 Tools and software for
3.2.6 Working of alignment algorithm 36 genome assembly 56
3.3 Scoring matrices: construction and 4.5.1 Genome finishing/polishing 56
proper selection 36 4.5.2 Assembly quality assessment and
3.3.1 Scoring matrices 36 validation 58
3.3.2 PAM matrices 37 4.6 Pitfall in genome assemblies 58
3.3.3 BLOSUM matrices 37 4.6.1 DNA quality 58
3.3.4 PAM versus BLOSUM 37 4.6.2 Library preparation 59
3.4 Basic Local Alignment Search Tool 38 4.6.3 Data quality 59
3.4.1 Seeding step 39 4.6.4 Repetitive DNA 59
3.4.2 Ungapped extension step 39 4.7 A mathematical calculation for depth/
3.4.3 Gapped extension step 39 coverage 60
3.4.4 Types of BLAST 39 4.8 Genome annotation 60
3.4.5 BLAT versus BLAST 39 4.8.1 Structural annotation 61
3.5 Multiple sequence alignment (MSA) 40 4.8.2 Functional annotation 62
3.5.1 Need for MSA 40 4.9 Application and future prospects of
3.5.2 Multiple sequence alignment genome assembly 62
algorithm 41 4.10 Conclusion 63
3.5.3 ClustalW 41 Conflict of interest 63
3.6 Phylogenetic analysis 42 References 63
3.6.1 Types of trees 43
3.6.2 Algorithms for phylogenetic analysis 43 5. Computational molecular phylogeny:
3.6.3 Terminology of phylogenetic tree 43 concepts and applications 67
3.7 Application of sequence alignment 44 Krishna Kumar Ojha, Swapnil Mishra
3.8 Conclusion 44 and Vijay Kumar Singh
Conflict of interest 45
References 45 5.1 Introduction 67
5.2 Convergent and divergent evolution 67
4. Genome assembly and annotation 49 5.3 Concept of cladistics and systematics 68
5.4 Phylogenetic trees’ terminology 69
Pallavi Mishra, Ranjeet Maurya,
5.4.1 Phylogenetic tree 69
Himanshu Avashthi, Shikha Mittal,
5.4.2 Taxon 69
Muktesh Chandra and
5.4.3 Node 69
Pramod Wasudeo Ramteke
5.4.4 Leaf 69
4.1 Introduction 49 5.4.5 Internal node 70
4.1.1 How do you reassemble a 5.4.6 Edge 70
genome after sequencing? 50 5.4.7 Topology 70
4.1.2 Assembler technology: historical 5.4.8 Root 70
landscape 50 5.4.9 Rooted tree 70
4.2 Genome assembly algorithms 51 5.4.10 Unrooted tree 70
4.2.1 The overlap-layout-consensus/string 5.4.11 Binary tree 70
graph assemblers 51 5.4.12 Clade 71
4.2.2 De Bruijn graph assemblers 51 5.4.13 Monophyletic taxon 71
 Contents vii

5.4.14 Paraphyletic taxon 71 6.7 Applications of RNA-sequencing 100

5.4.15 Polyphyletic taxon 71 6.8 Advantages of transcriptome
5.4.16 Split 72 sequencing over microarray technology 100
5.4.17 Subtree 72 6.9 Limitations and future perspective of
5.4.18 Edge length 72 RNA-sequencing 100
5.4.19 Ultrametric tree 72 6.10 Conclusion 100
5.4.20 Cladogram 73 Conflict of interest 101
5.4.21 Phylogram 73 References 101
5.4.22 Dendrogram 73
5.5 Evolutionary inference of phylogenetic 7. RNA-seq for revealing the function
trees 73 of the transcriptome 105
5.5.1 Importance of shared derived
characters in phylogeny 74 Kavita Goswami and Neeti Sanan-Mishra
5.6 Tree construction methods 74 7.1 Introduction 105
5.6.1 UPGMA 74 7.2 Next-generation sequencing platforms
5.6.2 Neighbor-joining algorithm 76 and their technologies 105
5.6.3 Maximum parsimony 80 7.2.1 Illumina 106
5.6.4 Maximum likelihood phylogeny 82 7.2.2 Roche 454 106
5.6.5 Bayesian phylogeny 83 7.2.3 ION torrent 107
5.7 Estimating reliability of phylogenetic tree 84 7.2.4 SoLid ABI 107
5.7.1 Bootstrapping 85 7.2.5 Illumina Tru-seq SLR technology 108
5.8 Phylogenetic tools 85 7.2.6 Pacific Biosciences (PacBio)
5.9 Application of molecular phylogeny 86 SMRT sequencing 108
5.9.1 Classification 86 7.2.7 Oxford Nanopore 108
5.9.2 Identifying the origin of pathogens 87 7.3 Analyzing the RNA-seq data 109
5.9.3 Species conservation 87 7.3.1 Quality and depth of raw
5.10 Conclusion 87 sequencing data 109
Conflict of interest 87 7.3.2 Adapter removal 110
References 87 7.3.3 Level of alignment 110
7.3.4 Redundancy rate of reads 111
6. Applications and challenges of 7.4 RNA-seq applications 111
microarray and RNA-sequencing 91 7.4.1 Transcriptome assembly 111
7.4.2 Identification of novel
Ankita Negi, Abhimati Shukla, Akanksha Jaiswar,
protein-coding genes 112
Jatin Shrinet and Rahul Singh Jasrotia
7.4.3 Identification of other classes of
6.1 Introduction 91 RNAs 113
6.2 Evolution of microarray 92 7.4.4 Profiling expression patterns 115
6.2.1 Automated arrays and cDNA 7.4.5 Degradome sequencing 119
cloning to microarray technology 92 7.4.6 Variants detection and
6.2.2 Principle of microarray 92 allele-specific expression 120
6.2.3 List of microarray tools and their 7.4.7 Expression quantitative trait loci 120
utility 94 7.5 Databases and software for small
6.3 DNA sequencing 94 RNA analysis 121
6.3.1 First generation 94 7.5.1 miRBase 121
6.3.2 Second generation 95 7.5.2 PMRD 121
6.3.3 Third generation 96 7.5.3 Armour 121
6.4 RNA-sequencing 96 7.5.4 UEA sRNA workbench 121
6.4.1 Library preparation and sequencing 96 7.5.5 sRNAtoolbox 122
6.4.2 Pipeline and usage of RNA- 7.5.6 sRNAbench 122
sequencing 97 7.5.7 miRNAconsTarget 122
6.5 Biological databases for 7.5.8 Massively parallel signature
data submission 99 sequencing database 122
6.6 Applications of microarray 99 7.5.9 CLC Genomics Workbench 122
viii Contents

7.6 Conclusion 122 9.3.5 DEEPred 149

Conflict of interest 123 9.3.6 SDNGO 149
References 123 9.3.7 AmiGO 149
9.3.8 OBO-Edit 149
8. Analysis of SSR and SNP markers 131 9.3.9 Gene Ontology Functional
Enrichment Annotation Tool 149
Ankita Mishra, Pramod Kumar Singh,
9.4 GO enrichment analysis 149
Abhishek Bhandawat, Vinay Sharma, Vikas Sharma,
9.4.1 DAVID (Database for Annotation,
Pradeep Singh, Joy Roy and Himanshu Sharma
Visualization, and Integrated
8.1 Introduction 131 Discovery) 150
8.2 Analysis of SSR markers 132 9.4.2 PANTHER (Protein ANalysis
8.2.1 Benefits and limitations of THrough Evolutionary
microsatellite markers 132 Relationships) 150
8.2.2 SSR mining and primer designing 133 9.4.3 g:Profiler 150
8.2.3 Classification and genomic 9.4.4 clusterProfiler 151
localization 133 9.4.5 Enrichr 151
8.2.4 Functional annotations of SSR 9.4.6 ToppGene 151
containing sequences 133 9.4.7 QuickGo 152
8.2.5 SSR amplification and evaluation of 9.4.8 REVIGO (Reduce & Visualize
polymorphic potential 133 Gene Ontology) 152
8.2.6 Cross-transferability of SSR markers 134 9.4.9 WEGO (Web Gene Ontology) 152
8.2.7 Future perspective 135 9.4.10 ShinyGO 152
8.3 Analysis of SNP markers 135 9.4.11 ViSEAGO 152
8.3.1 Approaches for sequence data 9.4.12 PoGo (Prediction of
generation 135 Gene Ontology) 152
8.3.2 Sample preparation 135 9.4.13 GOrilla (Gene Ontology
8.3.3 Sequencing of complex genomes 135 enRIchment anaLysis and
8.3.4 Assessment of sequence quality 136 visuaLizAtion tool) 152
8.3.5 Reads assembly and mapping to 9.4.14 EasyGO 152
reference genome 136 9.4.15 GOEAST (Gene Ontology
8.3.6 Postprocessing of mapped reads 138 Enrichment Analysis
8.3.7 Variant calling and filtration 138 Software Toolkit) 153
8.3.8 Functional annotation of variant 138 9.4.16 GOAT (Gene Ontology
8.4 Conclusion 140 Annotation Tool) 153
Acknowledgments 140 9.4.17 GOLEM (Gene Ontology Local
Conflict of interest 140 Exploration Map) 153
References 140 9.4.18 GOssTo (Gene Ontology
Further reading 144 semantic similarity Tool) 153
9.4.19 NaviGO 153
9. Gene Ontology: application and 9.5 Applications 153
importance in functional annotation 9.6 Future prospects 154
of the genomic data 145 9.7 Conclusion 154
Acknowledgment 154
Reshu Saxena, Ritika Bishnoi and Deepak Singla
Conflict of interest 155
9.1 Background 145 Author contributions 155
9.2 Gene Ontology based classification 146 References 155
9.2.1 Cellular component 147
9.2.2 Molecular function 147 10. Metagenomics: the boon for
9.2.3 Biological process 147 microbial world knowledge
9.3 Annotation of unknown gene/genome 147 and current challenges 159
9.3.1 Blast2GO 148
J.K. Choudhari, J. Choubey, M.K. Verma,
9.3.2 IPRscan (InterProScan) 148
T. Chatterjee and B.P. Sahariah
9.3.3 Genome Assembly and Annotation
Package 149 10.1 Introduction: an overview of
9.3.4 GOnet 149 metagenomics 159
 Contents ix

10.2 Resources in metagenomics 161 11.5.1 Mutation studies 185

10.3 Challenges in metagenomics 161 11.5.2 Unfolding studies 185
10.4 The workflow in metagenome analysis 162 11.5.3 Binding site prediction 185
10.5 Dataset acquire and processing 162 11.5.4 Protein docking and virtual
10.6 Quality control analysis 162 screening 185
10.6.1 Base quality score 162 11.5.5 Understanding the dynamics of
10.6.2 Sequence quality score 162 protein or protein ligand
10.6.3 Overrepresented sequences 163 complex 186
10.6.4 Per base N content 163 11.5.6 Structure evolution analysis 186
10.6.5 Duplicate sequences 163 11.6 Conclusion 186
10.6.6 Read length distribution 163 Conflict of interest 186
10.6.7 Per base sequence content 163 References 186
10.6.8 Guanine cytosine content 163 Further reading 188
10.6.9 Overrepresented k-mers 163
10.6.10 Quality analysis and improving 12. Structural and functional analysis
software tools 163 of protein 189
10.7 Genome assembly tools in
metagenomics 164 Neetu Singh Yadav, Pawan Kumar
10.8 Binning tools in metagenomics 164 and Indra Singh
10.8.1 Statistical analysis 166 12.1 Protein preliminaries 189
10.9 Data storage and sharing 166 12.2 Growth of the protein
10.10 Metagenomics analysis: a case study 166 structural database 189
10.11 Material, methodology, and outcome 166 12.3 Structural topology and fold
10.11.1 Metagenome dataset 166 classification scheme 190
10.11.2 Sequencing quality analysis 166 12.4 D-Structure quality
10.11.3 Hits distribution of metagenome assessment protocol 191
from the database sources 168 12.5 Protein 3D structure prediction 191
10.11.4 Hits distribution of functional 12.5.1 Energy functions 192
group 168 12.6 Machine learning in PSP 197
10.11.5 Taxonomic hits distribution 170 12.6.1 Feature engineering and
10.11.6 Rarefaction curve 170 representation 197
10.11.7 Alpha diversity 170 12.6.2 Feature selection 198
10.12 Advantages of metagenomics study 172 12.6.3 ML algorithms 198
10.13 Limitations and future perspective 172 12.6.4 ML models’ implementation
10.14 Conclusion 172 and evaluation 199
Conflict of interest 173 12.7 Conclusion 200
References 173 Conflict of interest 201
References 201
11. Protein structure prediction 177
13. Computational approaches in
Shikha Agnihotry, Rajesh Kumar Pathak,
Dev Bukhsh Singh, Apoorv Tiwari
drug designing 207
and Imran Hussain Anshul Tiwari and Sakshi Singh
11.1 Introduction 177 13.1 Introduction 207
11.2 Protein structure prediction 177 13.2 Computer-aided drug designing 207
11.3 Method of protein structure prediction 178 13.2.1 Structure-based drug design 207
11.3.1 Homology modeling 13.2.2 Ligand-based drug design 209
(comparative modeling) 178 13.3 Computational approaches 209
11.3.2 Threading or fold recognition 180 13.3.1 Molecular modeling 209
11.3.3 Ab initio approach 182 13.3.2 Binding site and cavity
11.4 Evaluation of predicted prediction 211
protein structure 184 13.3.3 Computational ligand
11.5 Applications of structure prediction 185 designing and searching 211
x Contents

13.3.4 Pharmacophore modeling 211 15.3.2 Conformational flexibility 236

13.3.5 Molecular docking 211 15.3.3 Scaffold hopping 236
13.3.6 Molecular dynamics simulation 212 15.3.4 Fragment-based drug design 236
13.3.7 Quantitative structure activity 15.4 Pharmacophore mapping 236
relationship 213 15.4.1 Diverse conformation
13.3.8 Lead optimization 214 generation 236
13.4 Limitations 214 15.4.2 Generation of 3D
13.5 Recent trends in drug designing 214 pharmacophore 237
13.6 Conclusion 215 15.4.3 Validation of the
Conflict of interest 215 pharmacophore model 237
References 215 15.5 Pharmacophore classifications 238
15.5.1 Ligand-based pharmacophore
14. Structure-based drug designing 219 modeling 238
Shubham Pant, Shivani Verma, 15.5.2 Structure-based pharmacophore
Rajesh Kumar Pathak and Dev Bukhsh Singh modeling 239
15.6 Application of pharmacophore in
14.1 Introduction 219 virtual screening and de novo design 239
14.2 Background of structure-based drug 15.6.1 Virtual screening 239
design 220 15.6.2 De novo pathway 240
14.3 Process of SBDD 221 15.7 Advancement in exploring 3D
14.3.1 Target identification 221 pharmacophore principles over
14.3.2 Target structure the above limitations 240
determination/prediction 221 15.8 Quantitative structure activity
14.3.3 Cavity/binding site prediction 223 relationship 240
14.3.4 Ligand structure preparation/ 15.8.1 Designation of QSAR 241
retrieval 223 15.8.2 Backbone of chemical
14.3.5 Molecular docking and virtual similarity 241
screening 224 15.8.3 QSAR data 242
14.3.6 ADMET analysis 226 15.8.4 Classification of 3D QSAR
14.3.7 Molecular dynamics simulation 226 approaches 243
14.3.8 Binding-free-energy 15.8.5 Molecular interactions and
calculation-MM-PBSA 227 energies 243
14.4 Recent development in SBDD 227 15.8.6 QSAR modeling 245
14.5 Challenges and limitations 228 15.8.7 Concept of applicability
14.6 Future prospective 228 domain and QSAR approaches 246
14.7 Conclusion 229 15.9 Development of new QSAR: HQSAR 248
Conflict of interest 229 15.10 Application of QSAR/SAR 248
References 229 15.10.1 Synthetic organic chemistry
and QSAR 248
15. Ligand-based drug designing 233 15.10.2 Prediction of kinetic and
thermodynamic parameters 249
Suchitra M. Ajjarapu, Apoorv Tiwari,
15.10.3 Drug development and other
Pramod Wasudeo Ramteke, Dev Bukhsh Singh
applications 249
and Sundip Kumar
15.11 Conclusion 250
15.1 Introduction 233 Conflict of interest 250
15.2 Pharmacophore 234 References 250
15.2.1 Build pharmacophore
hypothesis 234
15.2.2 Alignment of molecules 235 16. Discovery and optimization of lead
15.2.3 Similarity search methods 235 molecules in drug designing 253
15.2.4 2D finger prints 235
Shivani Verma and Rajesh Kumar Pathak
15.3 3D fingerprints 235
15.3.1 3D similarities depend on the 16.1 Introduction 253
alignment 236 16.2 Principles of CADD 254
 Contents xi

16.2.1 Case study: inhibition of 17.5.2 Prediction of pharmacokinetic

lipoxygenases 255 properties 279
16.3 Discovery of the lead molecule 256 17.5.3 Target identification and de novo
16.4 Types of lead molecules 256 ligand design using
16.4.1 Natural lead compounds 256 pharmacophore approaches 279
16.4.2 Synthetic lead molecules 257 17.5.4 Protein functionality studies 279
16.4.3 Semisynthetic drugs 259 17.5.5 3D pharmacophore modeling
16.5 Lead optimization and strategies 259 using a web platform 279
16.5.1 By using organic synthetic 17.5.6 Pharmacophore methods in
chemistry 259 light of molecular dynamics
16.5.2 Structure simplification 261 simulations 280
16.5.3 Structure modification 261 17.6 Applications of pharmacophore
16.5.4 Functional group interconversion 261 modeling 281
16.5.5 Bonding strength and selectivity 262 17.6.1 Generation of e-pharmacophore
16.5.6 Using thermodynamic, for virtual screening of drug
pharmacodynamics, and molecules 281
pharmacokinetic parameters 262 17.6.2 ADME-Tox analysis 282
16.6 Computational lead optimization 263 17.6.3 Generation of a multitarget
16.7 Advantages of computational lead ligand 282
designing 263 17.6.4 Modulation of the immune
16.8 Future perspectives 263 system 282
16.9 Conclusion 264 17.6.5 Pharmacophore-guided drug
Conflict of interest 265 target identification 282
References 265 17.7 Future perspectives of pharmacophore
models 283
17. Pharmacophore modeling and its 17.7.1 Fragment-based drug design 283
applications 269 17.7.2 Protein protein interaction
inhibition 283
Rashmi Tyagi, Amisha Singh, Kamal Kumar
17.7.3 A potential role in protein design 283
Chaudhary and Manoj Kumar Yadav
17.8 Conclusion 284
17.1 Introduction 269 Conflict of interest 284
17.2 Basics of pharmacophore modeling 271 References 284
17.2.1 Division of initial data into
diverse datasets 271 18. Molecular docking and molecular
17.2.2 Conformational analysis with dynamics simulation 291
three-dimensional structures 272
Sakshi Singh, Qanita Bani Baker
17.3 Different methods of pharmacophore
and Dev Bukhsh Singh
generation 273
17.3.1 Ligand-based pharmacophore 18.1 Introduction 291
modeling 273 18.2 Molecular docking 292
17.3.2 Structure-based pharmacophore 18.2.1 Algorithms 292
modeling 275 18.2.2 Scoring functions 294
17.4 Validation of pharmacophore models 276 18.2.3 Knowledge-based SFs 294
17.4.1 Receiver operating characteristic 18.3 Docking methodologies 295
curve 276 18.3.1 Flexible docking 295
17.4.2 Structure-based pharmacophore 18.3.2 Semiflexible docking 295
modeling approach for the design 18.3.3 Virtual screening of
of azaindole derivatives as DprE1 high-throughput docking 295
inhibitors for tuberculosis: 18.3.4 Fragment docking 296
a case study 277 18.3.5 Machine learning in docking 296
17.5 Recent trends in pharmacophore 18.3.6 Docking tools and their features 297
generation 278 18.4 Molecular dynamics simulation 297
17.5.1 Machine-learning models 18.4.1 Postdocking refinement 298
incorporated with pharmacophore 18.4.2 Binding-free energy calculations:
descriptors 278 MM-GBSA/MM-PBSA 299
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xii Contents

18.5 Challenges in molecular docking and 20.3.2 Prediction of linear B-cell

MD simulation techniques 300 epitopes 321
18.6 Conclusion 301 20.4 In silico method for T-cell epitope
Conflict of interest 301 prediction 322
References 301 20.4.1 MHC class I binder prediction 323
20.4.2 MHC class II binder prediction 324
19. Pharmacokinetics and 20.4.3 MHC gene diversity and its
pharmacodynamics analysis of importance in T-cell epitope
drug candidates 305 prediction 325
20.5 Adjuvant and linker selection 325
Satendra Singh, Dev Bukhsh Singh, 20.6 Building 3D model and validation of
Budhayash Gautam, Anamika Singh fusion vaccine construct 326
and Namrata Yadav 20.7 Miscellaneous properties 326
19.1 Introduction 305 20.7.1 Peptide toxicity 326
19.2 Postgenomic era and drug discovery 306 20.7.2 Half-life or stability 327
19.3 Pharmacokinetics 307 20.7.3 Delivery methodology 327
19.3.1 Drug absorption 308 20.8 Role of next-generation sequencing
19.3.2 Drug distribution (binding/ technology in vaccine design 328
localization/storage) 308 20.9 Computer-aided vaccine
19.3.3 Drug metabolism 309 development example 328
19.4 Pharmacodynamics 311 20.10 Conclusion 329
19.4.1 Drug toxicity 311 Acknowledgments 329
19.5 Computational approaches for Conflict of interest 330
ADMET prediction 311 References 330
19.6 Translational bioinformatics 313
19.7 Drug repurposing 313 21. Metabolomics and flux balance
19.7.1 Benefits of drug repurposing 313 analysis 337
19.7.2 Computational drug repurposing 314
19.8 Role of pharmacogenomics in Priyanka Narad, G. Naresh
precision medicine 314 and Abhishek Sengupta
19.9 Chemical diversity of natural 21.1 Introduction 337
products: a source for computer-aided 21.2 Definition of metabolomics 338
drug discovery 315 21.3 MS- and NMR-based techniques in
19.10 Conclusion 315 metabolomics 338
Conflict of interest 315 21.4 Data processing in metabolomics 339
References 315 21.4.1 Nuclear magnetic resonance
Further reading 316 spectroscopy 339
21.4.2 Workflow of MS-based
20. Computational approaches for metabolomics 339
vaccine designing 317 21.4.3 Limitations of NMR and MS
methods 340
Animesh Awasthi, Gaurav Sharma
21.4.4 Recent advances in MS- and
and Piyush Agrawal
NMR-based metabolomics 341
20.1 Introduction 317 21.4.5 Challenges and affecting factors 341
20.2 Antigen selection and immunological 21.5 Applications of metabolomics 341
databases 318 21.5.1 Microbial science 341
20.2.1 Exogenous antigens 318 21.5.2 Plant science 341
20.2.2 Endogenous antigens 319 21.5.3 Animal science 342
20.2.3 Autoantigens 319 21.5.4 Medical science 342
20.3 In silico method for B-cell epitope 21.5.5 Food and herbal medicines 343
prediction 319 21.6 Flux balance analysis 343
20.3.1 Prediction of conformational 21.7 Metabolic networks and model
B-cell epitopes 320 construction 344
 Contents xiii

21.7.1 Metabolic model: construction 22.4.1 Graph theory 371

and refinement 345 22.4.2 Adjacency matrices 373
21.7.2 Mass balance 348 22.5 Topological parameters 373
21.7.3 Steady state 349 22.5.1 Node degree 374
21.7.4 Types of constraints 349 22.5.2 The average of shortest
21.7.5 Optimization 350 path length 374
21.7.6 Steps in FBA 351 22.5.3 Clustering coefficient 375
21.8 Metabolic control analysis and isotopic 22.5.4 Betweenness centrality 375
steady state/carbon flux analysis 352 22.5.5 Statistical comparison 375
21.8.1 Metabolic control analysis 352 22.6 Biological significance of
21.8.2 Carbon flux analysis 352 network motifs 375
21.8.3 Different types of flux balance 22.7 Applications of network biology 376
analysis at different conditions 353 22.8 Limitations and challenges 376
21.9 Some important tools of flux balance 22.9 Conclusion 376
analysis 355 Conflict of interest 377
21.9.1 OptKnock 355 References 377
21.9.2 OptGene 355
21.9.3 OptStrain 356 23. Network biology and applications 381
21.9.4 COBRA Toolbox 356
21.9.5 MetaboAnalyst 4.0 356 Neeru Redhu and Zoozeal Thakur
21.9.6 OptFlux 356 23.1 Introduction to biological networks 381
21.9.7 OpenFlux 357 23.2 Biological networks properties 381
21.9.8 CellNetAnalyzer 357 23.2.1 Path, average path length,
21.9.9 SBRT 357 and diameter 381
21.9.10 Escher-FBA 357 23.2.2 Degree aka connectivity 382
21.9.11 MetaFluxNet 357 23.2.3 Scale free 382
21.10 Applications, challenges, and future 23.2.4 Small world network 382
perspectives of FBA 358 23.2.5 Date and party hub 382
21.10.1 Applications 358 23.2.6 Network motifs 382
21.10.2 Challenges and future 23.3 Types of biological networks 382
perspectives 360 23.3.1 Ecological networks 383
21.11 Case study: applications of 23.3.2 Gene (genetic) regulatory
metabolomics and flux balance network 383
analysis in industrially important 23.3.3 Protein protein interaction
microorganisms 361 network 384
21.11.1 Lactococcus lactis 361 23.3.4 Metabolic networks 385
21.11.2 Saccharomyces cerevisiae 361 23.3.5 Cellular signaling network 385
21.11.3 Escherichia coli 362 23.3.6 Gene coexpression network 387
21.12 Conclusion 363 23.4 Experimental methods in network
References 363 biology 387
23.4.1 Microarray 387
22. Topological parameters, patterns, 23.4.2 Deep mRNA sequencing 388
and motifs in biological networks 367 23.4.3 Exome sequencing 388
23.4.4 ChIP-seq 389
Arvind Kumar Yadav, Rohit Shukla
23.4.5 Genome-wide bisulfite
and Tiratha Raj Singh
sequencing 389
22.1 Introduction 367 23.4.6 Yeast two-hybrid 390
22.2 Biological networks 368 23.4.7 Mass spectrometry-based
22.2.1 Construction of biological proteomics 391
networks 368 23.4.8 Flow and mass cytometry 392
22.3 Network motifs and patterns 369 23.4.9 Live cell imaging 392
22.3.1 Motif discovery and counting 369 23.5 Resources for biological
22.4 Analysis of biological network 370 network-based studies 393
xiv Contents

23.5.1 Kyoto Encyclopedia of Genes 24.5 Platforms used for modeling and
and Genomes 393 simulations 415
23.5.2 BioCyc Database Collection 393 24.5.1 Pathway designing tools 415
23.5.3 ENZYME 393 24.5.2 Pathway Tools 415
23.5.4 ExplorEnz: the enzyme database 394 24.5.3 Simulation tools 416
23.5.5 Biochemical Genetic and 24.6 Applications of pathway modeling and
Genomic/Biochemical Genetic simulations 418
and Genomic models 394 24.6.1 Metabolic engineering 418
23.5.6 STRING 394 24.6.2 Drug designing 418
23.5.7 metaTIGER 394 24.6.3 Study of phenomics 419
23.6 Tools for network pathway analysis 394 24.6.4 Flux balance analysis 419
23.6.1 Pathway tools 395 24.7 Challenges 420
23.6.2 ERGO 395 24.7.1 Knowledge gaps between
23.6.3 KEGGtranslator 395 computationalists and
23.6.4 ModelSEED 395 experimentalists 420
23.6.5 Network Analysis Tools 396 24.7.2 Theory development 420
23.6.6 BioNetStat 396 24.7.3 Miscellaneous computational
23.6.7 OmicsNet 396 challenges 420
23.7 Applications of network biology 396 24.8 Conclusion 420
23.7.1 Applications in rare diseases 396 Conflict of interest 421
23.7.2 Determination of References 421
protein function 398
23.7.3 Pathway determination 398 25. Systems biology and big data
23.7.4 Essential protein identification 398 analytics 425
23.7.5 Functional modules’
identification 399 Rohit Shukla, Arvind Kumar Yadav,
23.8 Challenges and future perspective 399 William O. Sote, Moacyr Comar Junior
23.8.1 Pseudo temporal ordering 399 and Tiratha Raj Singh
23.8.2 Multiple data sources 400 25.1 Introduction 425
23.8.3 Combination of algorithms 400 25.2 Big data in general and in the context
23.9 Conclusion 400 of biology 425
Conflict of interest 401 25.3 Types of data in systems biology 426
References 401 25.3.1 Biological sequences 428
25.3.2 Molecular structure 428
24. Pathway modeling and simulation 25.3.3 Gene expression 428
analysis 409 25.3.4 Binding sites and domains 429
25.3.5 Protein protein interaction 429
Gitanjali Tandon, Sunita Yadav
25.3.6 Mass spectroscopy 429
and Sukhdeep Kaur
25.3.7 Metabolic pathways 429
24.1 Introduction 409 25.4 Biological big data resources 429
24.2 Computational modeling of 25.4.1 Genomics and transcriptomics
a pathway 409 resources 430
24.2.1 Type of modeling 410 25.4.2 Proteomics resources 430
24.2.2 Approaches of modeling 410 25.4.3 Cellular metabolome 430
24.3 General diagram and language used in 25.4.4 Protein protein interaction
pathway modeling 411 databases 430
24.3.1 Systems Biology Graphical 25.4.5 Drug and chemical compound
Notation 411 databases 432
24.3.2 Systems Biology Markup 25.4.6 Different other databases 432
Language 412 25.5 Network generation and its analysis
24.4 Pathway simulations analysis 413 from various sources of data 432
24.4.1 Ordinary differential equations 413 25.6 Big data in drug repurposing and
24.4.2 Stochastic simulation 414 systems pharmacology 434
 Contents xv

25.6.1 Network-based approaches for 27.3.2 Estimation 458

systems pharmacology 435 27.3.3 Prediction 459
25.7 Case study related to transcriptome 27.3.4 Association 459
data analysis 435 27.3.5 Clustering 459
25.8 Limitations in big data analysis 437 27.3.6 Description and visualization 460
25.9 Conclusion 438 27.3.7 Case studies using Waikato
Acknowledgment 438 environment for knowledge
Conflict of interest 438 analysis 461
References 438 27.4 Feature selection technique in data
mining 461
26. Machine learning in bioinformatics 443 27.4.1 Objective of feature selection 462
27.5 Major data mining algorithms
Indrajeet Kumar, Surya Pratap Singh applicable to biological data 462
and Shivam 27.5.1 C4.5 algorithm 462
26.1 Introduction 443 27.5.2 K-means algorithm 462
26.2 Supervised learning 443 27.5.3 Support vector machine 463
26.2.1 Classification 444 27.6 Biological data evolution and related
26.2.2 Supervised machine learning in issues 463
bioinformatics 444 27.6.1 Biological data availability 463
26.3 Unsupervised machine learning 445 27.6.2 Biological data availability in
26.4 Problems to understand supervised computer-readable form 464
learning and unsupervised learning 446 27.6.3 Biological data cleaning 464
26.5 Regression 446 27.6.4 Biological data quality 464
26.5.1 Hypothesis 447 27.6.5 Biological data dimensionality 464
26.6 Clustering 450 27.6.6 Biological data knowledge
26.6.1 K-means clustering 450 discovery 466
26.6.2 Density-based clustering 450 27.7 Bioinformatics research areas and tools 466
26.6.3 Distribution-based clustering 451 27.7.1 Sequence searching, comparison,
26.6.4 Fuzzy clustering 451 and evolutionary analysis 467
26.7 Unsupervised learning in 27.7.2 Annotation of gene/protein
bioinformatics 452 structure and function 467
26.8 Application of machine learning 452 27.7.3 Gene and protein expression
26.8.1 Genome annotation 452 analysis 468
26.8.2 Protein structure prediction 452 27.7.4 Mutation and disease association
26.8.3 Research area in bioinformatics study 468
with deep learning 453 27.7.5 Protein structure prediction,
26.9 Discussion 453 docking, and protein protein
26.10 Conclusion 454 interaction analysis 468
Conflict of interest 454 27.7.6 Biological systems modeling
References 454 and network analysis 468
27.7.7 Expressed sequence tag analysis 469
27. Bioinformatics and biological 27.7.8 MicroRNA and target prediction 469
27.7.9 Medical and health data analysis
data mining 457
and clinical decision support
Aditya Harbola, Deepti Negi, system 469
Mahesh Manchanda and 27.8 Limitations 469
Rajesh Kumar Kesharwani 27.9 Conclusion 470
Conflict of interest 470
27.1 Biological data mining 457
References 470
27.2 Data mining applications 457
27.3 Data mining process 458
Index 473
27.3.1 Classification 458
List of contributors

Shikha Agnihotry Department of Computational Biology and Bioinformatics, Jacob Institute of Biotechnology and
Bio-Engineering, Sam Higginbottom University of Agriculture, Technology and Sciences, Allahabad, India
Piyush Agrawal Centre for Computational Biology, Indraprastha Institute of Information Technology Delhi (IIITD),
Okhla Phase III, New Delhi, India
Suchitra M. Ajjarapu Bioinformatics Sub-DIC, Molecular Biology & Genetic Engineering, College of Basic Science
and Humanities, G.B. Pant University of Agriculture and Technology, India; Department of Biotechnology, Andhra
University, India
Himanshu Avashthi Department of Computational Biology & Bioinformatics, Sam Higginbottom University of
Agriculture Technology & Sciences, India; Division of Genomic Resources, ICAR National Bureau of Plant Genetic
Resources, Pusa Campus, New Delhi, India
Animesh Awasthi Institute of Bioinformatics and Applied Biotechnology (IBAB), Bengaluru, India; Department of
Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, India
Qanita Bani Baker Department of Computer Science, Jordan University of Science and Technology, Irbid, Jordan
Abhishek Bhandawat Agri-Biotechnology Division, National Agri-Food Biotechnology Institute, Mohali, India
Ritika Bishnoi School of Agricultural Biotechnology, Punjab Agricultural University, Ludhiana, India
Muktesh Chandra Centre of Bioinformatics, Institute of Interdisciplinary Sciences, University of Allahabad,
Prayagraj, India
T. Chatterjee Raipur Institute of Technology, Raipur, India
Kamal Kumar Chaudhary School of Biosciences, IMS Ghaziabad University Courses Campus, India
J. Choubey Raipur Institute of Technology, Raipur, India
J.K. Choudhari Chhattisgarh Swami Vivekanand Technical University, Bhilai, India
Budhayash Gautam Department of Computational Biology and Bioinformatics, Jacob Institute of Biotechnology and
Bioengineering, SHUATS, Prayagraj, India
Kavita Goswami Plant RNAi Biology Group, International Centre for Genetic Engineering and Biotechnology, New
Delhi, India
Aditya Harbola School of Computing, Graphic Era Hill University, Dehradun, India
Imran Hussain School of Life and Allied Health Sciences, Glocal University, Saharanpur, India
Akanksha Jaiswar Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
Rahul Singh Jasrotia Department of Biological Sciences, Florida State University, FL, United States
Moacyr Comar Junior Campus Centro-Oeste, Department of Biochemistry, Federal University of Sao Joao Del Rei,
Minas Gerais, Brazil
Sukhdeep Kaur Department of Computational Biology and Bioinformatics, Sam Higginbottom University of
Agriculture, Technology and Sciences (SHUATS), Prayagraj, India
Rajesh Kumar Kesharwani Nehru Gram Bharati Deemed University, Prayagraj, India
Indrajeet Kumar Graphic Era Hill University, Dehradun, India
Pawan Kumar Bioinformatics Center, National Institute of Immunology, New Delhi, India

xvii
xviii List of contributors

Sundip Kumar Bioinformatics Sub-DIC, Molecular Biology & Genetic Engineering, College of Basic Science and
Humanities, G.B. Pant University of Agriculture and Technology, India
Mahesh Manchanda School of Computing, Graphic Era Hill University, Dehradun, India
Ranjeet Maurya CSIR-Institute of Genomics and Integrative Biology, India
Ankita Mishra Agri-Biotechnology Division, National Agri-Food Biotechnology Institute, Mohali, India
Bhawana Mishra Department of Chemistry, Central University of Haryana, Jant-Pali, Mahendergarh, Haryana, India
Pallavi Mishra Centre for Agriculture Bioinformatics, ICAR-Indian Agricultural Statistics Research Institute, India;
Department of Computational Biology & Bioinformatics, Sam Higginbottom University of Agriculture Technology
& Sciences, India
Swapnil Mishra Center for Bioinformatics, University of Allahabad, India
Shikha Mittal Division of Genomic Resources, ICAR National Bureau of Plant Genetic Resources, Pusa Campus,
New Delhi, India
Priyanka Narad Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
G. Naresh Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
Ankita Negi Centre for Agricultural Bioinformatics (CABin), ICAR-Indian Agricultural Statistics Research Institute
(IASRI), New Delhi, India
Deepti Negi School of Computing, Graphic Era Hill University, Dehradun, India
Krishna Kumar Ojha Department of Bioinformatics, Central University of South Bihar, India
Shubham Pant Electrochemical Process Engineering Division, CSIR-Central Electrochemical Research Institute,
Karaikudi, India
Rajesh Kumar Pathak School of Agricultural Biotechnology, Punjab Agricultural University, Ludhiana, India
Pramod Wasudeo Ramteke Department of Computational Biology and Bioinformatics, Jacob Institute of
Biotechnology and Bio-Engineering, Sam Higginbottom University of Agriculture, Technology and Sciences, India;
Department of Molecular Biology & Genetic Engineering, RTM Nagpur University, India; Department of Life
Sciences, Mandsaur University, India; Department of Biological Sciences, Sam Higginbottom University of
Agriculture Technology & Sciences, India; Faculty of Life Sciences, Mandsaur University, India
Neeru Redhu Department of Molecular Biology, Biotechnology & Bioinformatics, College of Basic Sciences &
Humanities, CCS Haryana Agricultural University, Hisar, India
Joy Roy Agri-Biotechnology Division, National Agri-Food Biotechnology Institute, Mohali, India
B.P. Sahariah Chhattisgarh Swami Vivekanand Technical University, Bhilai, India
Neeti Sanan-Mishra Plant RNAi Biology Group, International Centre for Genetic Engineering and Biotechnology,
New Delhi, India
Reshu Saxena Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple
University, Philadelphia, PA, Unites States; Current address: Department of Biological Sciences and Biotechnology,
Institute of Advanced Research (IAR), Gandhinagar, India
Abhishek Sengupta Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
Gaurav Sharma Institute of Bioinformatics and Applied Biotechnology (IBAB), Bengaluru, India
Himanshu Sharma Agri-Biotechnology Division, National Agri-Food Biotechnology Institute, Mohali, India
Parva Kumar Sharma Indian Council of Agricultural Research—Indian Agricultural Statistics Research Institute,
New Delhi, India
Vikas Sharma Department of Botany, Sant Baba Bhag Singh University, Khiala, India
Vinay Sharma Agri-Biotechnology Division, National Agri-Food Biotechnology Institute, Mohali, India
Shivam Graphic Era Hill University, Dehradun, India
Jatin Shrinet Department of Biological Sciences, Florida State University, FL, United States
 List of contributors xix

Abhimati Shukla Department of Biochemical Engineering, Harcourt Butler Technical University, Kanpur, India
Rohit Shukla Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology (JUIT),
Solan, India
Samvedna Shukla Molecular and Bioprospection Division, CSIR-Central Institute of Medicinal and Aromatic Plants,
Lucknow, India
Amisha Singh Department of Biotechnology, JAIN University, India
Anamika Singh Department of Botany, Maitreyi College, University of Delhi, New Delhi, India
Dev Bukhsh Singh Department of Biotechnology, Institute of Biosciences and Biotechnology, Chhatrapati Shahu Ji
Maharaj University, Kanpur, India
Indra Singh School of Biotechnology, Banaras Hindu University, Varanasi, India
Pradeep Singh Department of Biotechnology, Guru Nanak Dev University, Amritsar, India
Pramod Kumar Singh Department of Biosciences, Christian Eminent College, Indore, India
Rahul Singh Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania,
Philadelphia, PA, United States
Sakshi Singh Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University,
Varanasi, India
Satendra Singh Department of Computational Biology and Bioinformatics, Jacob Institute of Biotechnology and
Bioengineering, SHUATS, Prayagraj, India
Surya Pratap Singh Graphic Era Hill University, Dehradun, India
Tiratha Raj Singh Centre of Excellence in Healthcare Technologies and Informatics (CHETI), Department of
Biotechnology and Bioinformatics, Jaypee University of Information Technology (JUIT), Solan, India
Vijay Kumar Singh Department of Bioinformatics, Central University of South Bihar, India
Deepak Singla School of Agricultural Biotechnology, Punjab Agricultural University, Ludhiana, India
William O. Sote Campus Centro-Oeste, Department of Biochemistry, Federal University of Sao Joao Del Rei, Minas
Gerais, Brazil
Gitanjali Tandon Centre for Agricultural Bioinformatics (CABin), ICAR—Indian Agricultural Statistics Research
Institute (IASRI), New Delhi, India
Zoozeal Thakur Bacteriology Lab, National Research Centre on Equines, Hisar, India
Anshul Tiwari Channing Division of Network Medicine, Brigham and Woman Hospital, Harvard Medical School,
Boston, MA, United States; Dept. of Ophthalmology, King George’s Medical University, Lucknow, India
Apoorv Tiwari Department of Computational Biology and Bioinformatics, Jacob Institute of Biotechnology and Bio-
Engineering, Sam Higginbottom University of Agriculture, Technology and Sciences, India; Bioinformatics Sub-
DIC, Molecular Biology & Genetic Engineering, College of Basic Science and Humanities, G.B. Pant University of
Agriculture and Technology, Pantnagar, India
Rashmi Tyagi Centre for Drug Design Discovery and Development (C4D), SRM University, India
M.K. Verma Chhattisgarh Swami Vivekanand Technical University, Bhilai, India; National Institute of Technology
Raipur, Raipur, India
Shivani Verma Department of Chemistry, College of Basic Sciences & Humanities, G. B. Pant University of
Agriculture and Technology, Pantnagar, India
Arvind Kumar Yadav Department of Biotechnology and Bioinformatics, Jaypee University of Information
Technology (JUIT), Solan, India
Inderjit Singh Yadav School of Agricultural Biotechnology, Punjab Agricultural University, Ludhiana, India
Manoj Kumar Yadav Centre for Drug Design Discovery and Development (C4D), SRM University, India;
Department of Bioinformatics, SRM University, India
Namrata Yadav Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, India
xx List of contributors

Neetu Singh Yadav Department of Biochemical Engineering & Biotechnology, Indian Institute of Technology Delhi,
New Delhi, India; Department of Chemical & Biomolecular Engineering, Clemson University, Clemson, SC, United
States
Sunita Yadav Centre for Agricultural Bioinformatics (CABin), ICAR—Indian Agricultural Statistics Research
Institute (IASRI), New Delhi, India
Preface

Bioinformatics is recognized as the science of the 21st century, and a lot of research has been conducted and on-going
throughout the world in this field. An updated resource with respect to time is required for a better understanding of the
tremendous power of computational approaches and their application in solving complex biological problems. This
book covers the basic understanding of the bioinformatics topics as well as focuses on recent developments in the meth-
ods, tools, and approaches related to bioinformatics, which includes biological databases and their application, sequence
analysis and comparison, phylogeny, NGS data analysis, genome, and transcriptome assembly and annotation, gene
ontology, metagenomics studies, SNP and SSR identification and analysis, transcriptome analysis; microarray studies,
RNA-Seq data analysis, protein structure prediction, visualization, analysis and validation; pharmacophore modeling,
structure-based and ligand-based drug design, molecular docking, molecular dynamics simulation, optimization of lead
compounds, pharmacokinetics and pharmacodynamics modeling, in silico vaccine designing, pathway modeling and
simulation, network biology, metabolomics, and flux balance analysis, systems biology and big data analysis, machine
learning, and data mining approaches.
This book also covers the broad spectrum of computational analysis and case studies and enables the reader to find
information about various bioinformatics methods, tools, and their applications in a single resource. Bioinformatics has
a very broad range of applications, and this field is upgrading very rapidly as many new resources and approaches are
being developed day by day. The chapters of this book have been compiled considering the diverse applications of this
field. This book can serve as a very useful learning source for undergraduate, postgraduate, and research students of
bioinformatics, biotechnology, life sciences, and agricultural sciences, chemical, pharmaceutical, and medical sciences
who have no computational background. Besides, it is also useful for bioinformatics and computer science students,
research scientists, and pharmaceutical persons to understand the fundamental concepts of bioinformatics and utilize
this knowledge to tackle research projects. However, in spite of the best efforts, the first version of a book always has
some opportunities to improve. We will be happy to receive the important suggestions for further improvements in the
content coverage.

xxi
Chapter 1

Introduction to basics of bioinformatics

Rajesh Kumar Pathak1, Dev Bukhsh Singh2 and Rahul Singh3
1
School of Agricultural Biotechnology, Punjab Agricultural University, Ludhiana, India, 2Department of Biotechnology, Institute of Biosciences and
Biotechnology, Chhatrapati Shahu Ji Maharaj University, Kanpur, India, 3Department of Basic and Translational Sciences, School of Dental
Medicine, University of Pennsylvania, Philadelphia, PA, United States

1.1 Introduction
Researchers are now constantly making efforts to explore the function of the biological system. Efforts are only at a
stage of unprecedented development and growth, expressed in the amount of data produced from each experiment
(Avashthi et al., 2014; Kumar, Pathak, Gupta, Gaur, & Pandey, 2015; Mount, 2001). Via bioinformatics, these huge
datasets from the experiments are turned into usable information (Mount, 2001; Wang, Zaki, Toivonen, & Shasha,
2005). Bioinformatics is recognized as the science of the 21st century and has tremendous potential for decoding com-
plex biological systems via analysis and integration of multiomics data. It uses information technology (IT) to allow
various types of biological data to be analyzed, linked, and manipulated to understand new biological insights
(Avashthi et al., 2020; Kumar et al., 2015; Pathak, Taj, Pandey, Arora, & Kumar, 2013).
In other words, bioinformatics is a data management and manipulation method for molecular biology, biochemistry,
the health sector, environmental biology, and agriculture, addressing the storage of data sets, data mining and proces-
sing, structural and functional annotations of gene and protein, system modeling, and drugs’ discovery (Avashthi et al.,
2018; Jayaram & Priyanka, 2010; Verma, Pathak, Kasana, & Kumar, 2017). It is used to predict the structure and func-
tion of a newly examined protein and protein sequences to create a cluster of similar family sequences and construct
phylogenetic trees for the study of evolutionary relationships (Jayaram & Priyanka, 2010; Mount, 2001; Wang et al.,
2005). Bioinformatics has a very important role to play in agriculture-dependent countries, where it can be used to boost
nutritional content, increase agricultural produce yields, and implant resistance to many biotic and abiotic stresses
(Jayaram & Priyanka, 2010; Meidanis, 2003; Pathak, Giri, Taj, & Kumar, 2013).
For the agricultural science sector, plant and animal genome sequencing should have an enormous yield. In both the
integration and analysis of genomics, transcriptomics, and other high-throughput sequencing results, bioinformatics plays
a vital role, with great potential in redesigning to boost productivity. To understand the function and interaction of many
genes, there has been a paradigm change from the single-gene approach (i.e., gene-by-gene approach) (Kumar et al.,
2015). This change has resulted from the discovery that cross-talking of several biomolecules acting in an interdependent
manner and results in any biological answer. As a consequence, several high-throughput technologies have been developed
that offer insight into all the molecules involved in a process (Kumar et al., 2015). Study in the field of genomics has
accelerated the process. There is, however, a large difference in the expression of a trait between the genotype and the
phenotype (Kumar et al., 2015; Pathak & Singh, 2020b). Studies are performed at various levels to fill this gap: the whole
system, organism, biochemical, gene, and protein levels. All these fields have contributed to the collection of vast amounts
of biological knowledge due to unprecedented research efforts. Bioinformatics, which culminates in biology and computa-
tional technology, aims to develop novel strategies for wide-scale analysis of biological system (Pathak & Singh, 2020a).
Bioinformatics techniques, such as simulation, docking, protein protein interaction, and analysis of next-generation
sequencing (NGS) data, may be used to investigate or modify the sequence for better fitting of essential genes for a par-
ticular function and to study the function of these genes or proteins at the system level. It was then possible to use this
specified genetic, genomic, and proteomic information to grow resistant, nutritionally improved, and profitable crops and
also discover therapeutic drugs (Agnihotry, Pathak, Srivastav, Shukla, & Gautam, 2020; Singh & Pathak, 2020). Some
important tools and databases along with their application and link of availability are highlighted in Tables 1.1 and 1.2.

Bioinformatics. DOI: https://doi.org/10.1016/B978-0-323-89775-4.00006-7

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The Project Gutenberg eBook of Three Stories
& Ten Poems
 This ebook is for the use of anyone anywhere in the United
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Title: Three Stories & Ten Poems

Author: Ernest Hemingway

Release date: May 25, 2019 [eBook #59603]

Language: English

Credits: Produced by an anonymous Project Gutenberg

volunteer.

*** START OF THE PROJECT GUTENBERG EBOOK THREE STORIES

& TEN POEMS ***
Copyright, 1923, by the author

Published by
Contact Publishing Co.
 THREE STORIES

Up In Michigan

Out of Season

My Old Man

& TEN POEMS

Mitraigliatrice

Oklahoma

Oily Weather

Roosevelt

Captives

Champs d’Honneur

Riparto d’Assalto
 Montparnasse

Along With Youth

Chapter Heading

ERNEST HEMINGWAY
 This Book
Is For Hadley
CONTENTS
Three Stories

Up In Michigan
Out Of Season
My Old Man

Ten Poems

Mitraigliatrice
Oklahoma
Oily Weather
Roosevelt
Captives
Champs D’Honneur
Riparto D’Assalto
Montparnasse
Along With Youth
Chapter Heading
Five of these poems were
first printed in Poetry
A Magazine of Verse.
UP IN MICHIGAN
 UP IN MICHIGAN

Jim Gilmore came to Hortons Bay from Canada. He bought the

blacksmith shop from old man Horton. Jim was short and dark with
big mustaches and big hands. He was a good horseshoer and did
not look much like a blacksmith even with his leather apron on. He
lived upstairs above the blacksmith shop and took his meals at A. J.
Smith’s.

Liz Coates worked for Smith’s. Mrs. Smith, who was a very large
clean woman, said Liz Coates was the neatest girl she’d ever seen.
Liz had good legs and always wore clean gingham aprons and Jim
noticed that her hair was always neat behind. He liked her face
because it was so jolly but he never thought about her.

Liz liked Jim very much. She liked it the way he walked over from
the shop and often went to the kitchen door to watch for him to
start down the road. She liked it about his mustache. She liked it
about how white his teeth were when he smiled. She liked it very
much that he didn’t look like a blacksmith. She liked it how much A.
J. Smith and Mrs. Smith liked Jim. One day she found that she liked
it the way the hair was black on his arms and how white they were
above the tanned line when he washed up in the washbasin outside
the house. Liking that made her feel funny.

Hortons Bay, the town, was only five houses on the main road
between Boyne City and Charlevoix. There was the general store and
postoffice with a high false front and maybe a wagon hitched out in
front, Smith’s house, Stroud’s house, Fox’s house, Horton’s house
and Van Hoosen’s house. The houses were in a big grove of elm
trees and the road was very sandy. There was farming country and
timber each way up the road. Up the road a ways was the Methodist
church and down the road the other direction was the township
school. The blacksmith shop was painted red and faced the school.
 A steep sandy road ran down the hill to the bay through the
timber. From Smith’s back door you could look out across the woods
that ran down to the lake and across the bay. It was very beautiful in
the spring and summer, the bay blue and bright and usually
whitecaps on the lake out beyond the point from the breeze blowing
from Charlevoix and Lake Michigan. From Smith’s back door Liz
could see ore barges way out in the lake going toward Boyne City.
When she looked at them they didn’t seem to be moving at all but if
she went in and dried some more dishes and then came out again
they would be out of sight beyond the point.

All the time now Liz was thinking about Jim Gilmore. He didn’t
seem to notice her much. He talked about the shop to A. J. Smith
and about the Republican Party and about James G. Blaine. In the
evenings he read the Toledo Blade and the Grand Rapids paper by
the lamp in the front room or went out spearing fish in the bay with
a jacklight with A. J. Smith. In the fall he and Smith and Charley
Wyman took a wagon and tent, grub, axes, their rifles and two dogs
and went on a trip to the pine plains beyond Vanderbilt deer
hunting. Liz and Mrs. Smith were cooking for four days for them
before they started. Liz wanted to make something special for Jim to
take but she didn’t finally because she was afraid to ask Mrs. Smith
for the eggs and flour and afraid if she bought them Mrs. Smith
would catch her cooking. It would have been all right with Mrs.
Smith but Liz was afraid.

All the time Jim was gone on the deer hunting trip Liz thought
about him. It was awful while he was gone. She couldn’t sleep well
from thinking about him but she discovered it was fun to think about
him too. If she let herself go it was better. The night before they
were to come back she didn’t sleep at all, that is she didn’t think she
slept because it was all mixed up in a dream about not sleeping and
really not sleeping. When she saw the wagon coming down the road
she felt weak and sick sort of inside. She couldn’t wait till she saw
Jim and it seemed as though everything would be all right when he
came. The wagon stopped outside under the big elm and Mrs. Smith
and Liz went out. All the men had beards and there were three deer
in the back of the wagon, their thin legs sticking stiff over the edge
of the wagon box. Mrs. Smith kissed Alonzo and he hugged her. Jim
said “Hello Liz.” and grinned. Liz hadn’t known just what would
happen when Jim got back but she was sure it would be something.
Nothing had happened. The men were just home that was all. Jim
pulled the burlap sacks off the deer and Liz looked at them. One was
a big buck. It was stiff and hard to lift out of the wagon.

“Did you shoot it Jim?” Liz asked.

“Yeah. Aint it a beauty?” Jim got it onto his back to carry to the
smokehouse.

That night Charley Wyman stayed to supper at Smith’s. It was too

late to get back to Charlevoix. The men washed up and waited in the
front room for supper.

“Aint there something left in that crock Jimmy?” A. J. Smith asked

and Jim went out to the wagon in the barn and fetched in the jug of
whiskey the men had taken hunting with them. It was a four gallon
jug and there was quite a little slopped back and forth in the bottom.
Jim took a long pull on his way back to the house. It was hard to lift
such a big jug up to drink out of it. Some of the whiskey ran down
on his shirt front. The two men smiled when Jim came in with the
jug. A. J. Smith sent for glasses and Liz brought them. A. J. poured
out three big shots.

“Well here’s looking at you A. J.” said Charley Wyman.

“That damn big buck Jimmy.” said A. J.

“Here’s all the ones we missed A. J.” said Jim and downed his
liquor.

“Tastes good to a man.”

 “Nothing like it this time of year for what ails you.”

“How about another boys?”

“Here’s how A. J.”

“Down the creek boys.”

“Here’s to next year.”

Jim began to feel great. He loved the taste and the feel of whisky.
He was glad to be back to a comfortable bed and warm food and the
shop. He had another drink. The men came in to supper feeling
hilarious but acting very respectable. Liz sat at the table after she
put on the food and ate with the family. It was a good dinner. The
men ate seriously. After supper they went into the front room again
and Liz cleaned off with Mrs. Smith. Then Mrs. Smith went up stairs
and pretty soon Smith came out and went up stairs too. Jim and
Charley were still in the front room. Liz was sitting in the kitchen
next to the stove pretending to read a book and thinking about Jim.
She didn’t want to go to bed yet because she knew Jim would be
coming out and she wanted to see him as he went out so she could
take the way he looked up to bed with her.

She was thinking about him hard and then Jim came out. His eyes
were shining and his hair was a little rumpled. Liz looked down at
her book. Jim came over back of her chair and stood there and she
could feel him breathing and then he put his arms around her. Her
breasts felt plump and firm and the nipples were erect under his
hands. Liz was terribly frightened, no one had ever touched her, but
she thought, “He’s come to me finally. He’s really come.”

She held herself stiff because she was so frightened and did not
know anything else to do and then Jim held her tight against the
chair and kissed her. It was such a sharp, aching, hurting feeling that
she thought she couldn’t stand it. She felt Jim right through the back
of the chair and she couldn’t stand it and then something clicked
inside of her and the feeling was warmer and softer. Jim held her
tight hard against the chair and she wanted it now and Jim
whispered, “Come on for a walk.”

Liz took her coat off the peg on the kitchen wall and they went
out the door. Jim had his arm around her and every little way they
stopped and pressed against each other and Jim kissed her. There
was no moon and they walked ankle deep in the sandy road through
the trees down to the dock and the warehouse on the bay. The
water was lapping in the piles and the point was dark across the bay.
It was cold but Liz was hot all over from being with Jim. They sat
down in the shelter of the warehouse and Jim pulled Liz close to
him. She was frightened. One of Jim’s hands went inside her dress
and stroked over her breast and the other hand was in her lap. She
was very frightened and didn’t know how he was going to go about
things but she snuggled close to him. Then the hand that felt so big
in her lap went away and was on her leg and started to move up it.

“Don’t Jim”. Liz said. Jim slid the hand further up.

“You musn’t Jim. You musn’t”. Neither Jim nor Jim’s big hand paid
any attention to her.

The boards were hard. Jim had her dress up and was trying to do
something to her. She was frightened but she wanted it. She had to
have it but it frightened her.

“You musn’t do it Jim. You musn’t.”

“I got to. I’m going to. You know we got to.”

“No we haven’t Jim. We aint got to. Oh it isn’t right. Oh it’s so big
and it hurts so. You can’t. Oh Jim. Jim. Oh.”

The hemlock planks of the dock were hard and splintery and cold
and Jim was heavy on her and he had hurt her. Liz pushed him, she
was so uncomfortable and cramped. Jim was asleep. He wouldn’t
move. She worked out from under him and sat up and straightened
her skirt and coat and tried to do something with her hair. Jim was
sleeping with his mouth a little open. Liz leaned over and kissed him
on the cheek. He was still asleep. She lifted his head a little and
shook it. He rolled his head over and swallowed. Liz started to cry.
She walked over to the edge of the dock and looked down to the
water. There was a mist coming up from the bay. She was cold and
miserable and everything felt gone. She walked back to where Jim
was lying and shook him once more to make sure. She was crying.

“Jim” she said, “Jim. Please Jim”.

Jim stirred and curled a little tighter. Liz took off her coat and
leaned over and covered him with it. She tucked it around him
neatly and carefully. Then she walked across the dock and up the
steep sandy road to go to bed. A cold mist was coming up through
the woods from the bay.
OUT OF SEASON
 OUT OF SEASON

On the four lira he had earned by spading the hotel garden he got
quite drunk. He saw the young gentleman coming down the path
and spoke to him mysteriously. The young gentleman said he had
not eaten yet but would be ready to go as soon as lunch was
finished. Forty minutes or an hour.

At the cantina near the bridge they trusted him for three more
grappas because he was so confident and mysterious about his job
for the afternoon. It was a windy day with the sun coming out from
behind clouds and then going under in sprinkles of rain. A wonderful
day for trout fishing.

The young gentleman came out of the hotel and asked him about
the rods. Should his wife come behind with the rods? Yes, said
Peduzzi, let her follow us. The young gentleman went back into the
hotel and spoke to his wife. He and Peduzzi started down the road.
The young gentleman had a musette over his shoulder. Peduzzi saw
the wife, who looked as young as the young gentleman and was
wearing mountain boots and a blue beret, start out to follow them
down the road carrying the fishing rods unjointed one in each hand.
Peduzzi didn’t like her to be way back there. Signorina, he called,
winking at the young gentleman, come up here and walk with us.
Signora come up here. Let us all walk together. Peduzzi wanted them
all three to walk down the street of Cortina together.

The wife stayed behind, following rather sullenly. Signorina,

Peduzzi called tenderly, come up here with us. The young gentleman
looked back and shouted something. The wife stopped lagging
behind, and walked up.

Everyone they met walking through the main street of the town
Peduzzi greeted elaborately. Buon’ di Arturo! Tipping his hat. The
bank clerk stared at him from the door of the Fascist café. Groups of
three and four people standing in front of the shops stared at the
three. The workmen in their stone-powdered jackets working on the
foundations of the new hotel looked up as they passed. Nobody
spoke or gave any sign to them except the town beggar, lean and
old with a spittle thickened beard, who lifted his hat as they passed.

Peduzzi stopped in front of a store with the window full of bottles

and brought his empty grappa bottle from an inside pocket of his old
military coat. A little to drink, some marsala for the Signora,
something, something to drink. He gestured with the bottle. It was a
wonderful day. Marsala, you like marsala, Signorina? A little marsala?

The wife stood sullenly. You’ll have to play up to this, she said. I
can’t understand a word he says. He’s drunk isn’t he?

The young gentleman appeared not to hear Peduzzi. He was

thinking what in hell makes him say Marsala. That’s what Max
Beerbohm drinks.

Geld, Peduzzi said finally, taking hold of the young gentleman’s

sleeve. Lire. He smiled reluctant to press the subject but needing to
bring the young gentleman into action.

The young gentleman took out his pocket book and gave him a
ten lire note. Peduzzi went up the steps to the door of the Speciality
of Domestic and Foreign Wines shop. It was locked.

It is closed until two, someone passing in the street said

scornfully. Peduzzi came down the steps. He felt hurt. Never mind,
he said, we can get it at the Concordia.

They walked down the road to the Concordia three abreast. On

the porch of the Concordia where the rusty bobsleds were stacked
the young gentleman said, Was wollen sie? Peduzzi handed him the
ten lira note folded over and over. Nothing, he said, Anything. He
was embarrassed. Marsala maybe. I don’t know. Marsala?
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