See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/352218450

Molecular Docking in Drug Discovery

Article in Journal of Pharmaceutical Research International · June 2021

DOI: 10.9734/jpri/2021/v33i30B31639

CITATIONS READS
12 9,135

7 authors, including:

Deepak Khobragade Sagar Wankhede

Datta Meghe Institute of Medical Sciences (Deemed University) JSPM's Charak College of Pharmacy and Research, Wagholi, Pune, India
44 PUBLICATIONS 188 CITATIONS 66 PUBLICATIONS 878 CITATIONS

SEE PROFILE SEE PROFILE

Ashwini Armarkar
Datta Meghe Institute of Pharmacy,Wardha
6 PUBLICATIONS 19 CITATIONS

SEE PROFILE

All content following this page was uploaded by Ashwini Armarkar on 18 September 2021.

The user has requested enhancement of the downloaded file.

 Journal of Pharmaceutical Research International

33(30B): 46-58, 2021; Article no.JPRI.68704

ISSN: 2456-9119
(Past name: British Journal of Pharmaceutical Research, Past ISSN: 2231-2919,
NLM ID: 101631759)

Molecular Docking in Drug Discovery

Rani T. Bhagat1*, Santosh R. Butle2, Deepak S. Khobragade1,
Sagar B. Wankhede1, Chandani C. Prasad1, Divyani S. Mahure1
and Ashwini V. Armarkar1
1
Datta Meghe College of Pharmacy, Datta Meghe Institute of Medical Sciences (Deemed to be
University) Salod, Sawangi, Wardha-442107, India.
2
School of Pharmacy, Swami Ramanand Teerth Marathwada University Nanded-431606, India.

Authors’ contributions

This work was carried out in collaboration among all authors. Author RTB designed overall study
about this manuscript and analyse the manuscript. Authors SRB, DSK and SBW wrote some part of
manuscript. Authors CCP and DSM she give suggestions at that time of manuscript preparation.
Author AVA spellings correction. All authors read and approved the final manuscript.

Article Information

DOI: 10.9734/JPRI/2021/v33i30B31639
Editor(s):
(1) Dr. Ana Cláudia Coelho, University of Trás-os-Montes and Alto Douro, Portugal.
Reviewers:
(1) Manish R.Bhise, Dr. Rajendra Gode college of Pharmacy, India.
(2) Hemant Kumar Singh Yadav, RAK Medical and Health Sciences University, United Arab Emirates.
(3) A Sanjeeva Kumar, Orotta College of Medicine and Health Sciences, Asmara, Eritrea.
Complete Peer review History: http://www.sdiarticle4.com/review-history/68704

Received 14 March 2021

Accepted 19 May 2021
Review Article
Published 03 June 2021

ABSTRACT

In last few years the Computer Aided Drug Design and Discovery is many success rates. In
academics and many pharmaceutical industries for drug lead discovery they adopt the
Computational Drug Design. The modern era of drug discovery and development structural
information play an important role. For visualization of 3D-structure of molecule different docking
program are developed. The docking score is analysed by using computer-based drug design
software. It is structure based virtual screening method for the orientation, conformation, position
into a structure of target molecule. Ligand and Protein docking is new concept. Molecular docking
method complication is optimization of lead molecule, biological pathway evaluation and de Novo
drug design.

Keywords: Molecular docking; binding; receptor; rigid; flexible.

_____________________________________________________________________________________________________

*Corresponding author: E-mail: [email protected];

 Bhagat et al.; JPRI, 33(30B): 46-58, 2021; Article no.JPRI.68704

1. INTRODUCTION 4. Discovery of in-silico filters for prediction of

undesirable properties like poor activity
The Suitable orientation of ligand molecule overs and poor Pharmacokinetic and Toxicity of
the receptor molecule to build a stable complex drug molecule.
is called as molecular docking [1-7]. This 5. It is used for the optimization of novel drug
orientation utilized for the binding affinity targets. CADD is being used to find hits
prediction and strength of connection of ligand 6. By using chemical scaffolds to find out
and protein by using scoring function. The drug novel Virtual screening is applied for new
receptor interaction predicts the affinity and drug molecules.
activity of molecule [8-17]. It plays vital role in
drug design and drug discovery. It is minimized 3. STRUCTURE-BASED DRUG DESIGN
overall free energy of system. New drug
discovery and development is very challenging Structure-based computer aided drug design
task. With the help of In-Silico method new drug depend on the knowledge of the target protein
discovery occurs [18-27]. For the rapid gaining of structure to calculate interaction energies for all
drug discovery process the computer-based drug tested compounds [43-46]. In structural data-
design should be used. It is useful in structural base is crystalized target proteins are available.
biology of molecule and computational drug structure- based is to design compounds that
design [28-35]. It is used to anticipate the 3- bind with minimal energy by specifically and
Dimensional structure of molecule. With the help tightly to the target [47-57]. A broader
of scoring function currently rank candidates terminology, Virtual high-throughput screening, is
docking for large libraries compound perform the a computer-based screening tool that allows
virtual screening [36-42]. screening of a large library of similar chemical
compounds for a particular biological activity
2. COMPUTER AIDED DRUG DESIGN [58-65]. Virtual high-throughput screening comes
in many forms, including: chemical similarity
It is computer-based technique used in the search, selecting compounds by predicted
computational chemistry to discover, enhance or biologic activity through quantitative structure-
study of drug and related biologically active activity relationship (QSAR) models or
molecule is called as (CADD) Computer Aided pharmacophore mapping, and virtual docking of
Drug Design. compounds against protein target of interest
[66-74]. By using computational tools in the lead
1. It is most useful in new drug design. optimization phase of drug development is
2. It provides knowledge about the chemical significant and cost benefit. Application of
and biological properties of ligands and computational tools in hit-to-lead optimization
targets. while reducing the number of compounds that
3. It is used to find and improve novel drug. must be synthesized and tested In vitro [75-79].

47
 Bhagat et al.; JPRI, 33(30B): 46-58, 2021;; Article no.JPRI.68704
no.

Fig. 1. Commuter aided drug design model

Target structure
Ligand Docking
Direct Drug
SBDD Design
de Novo design
Molecular docking
CADD

Pharmacophore Mapping
Ligand Structure information
Quantitative structure
Indirect Activity Relationship
LBDD Drug Design Pharmacophore Modelling
Ligand based Virtual
Screening

Fig. 2. Drug design structure

4. LIGAND-BASED
BASED DRUG DESIGN (1) For docking Preparation of the
e target protein
and compound library,
Ligand-based
based exploits the knowledge of known (2) Determining a Proper binding pose for each
active and inactive molecules for chemical compound, and
similarity searches or quantitative structure-
structure (3) Ranking the docked structures of molecules.
activity relation (QSAR). Ligand-based,
based, is ideal
To predicts the orientations or conformations of a
where the 3D structure of the target proteins are
receptor-ligand
ligand complex by using the Molecular
not available.
docking and it is a structural based computer
Structural-Based
Based Computer Aided Drug Design: simulation procedure and used to predict the
binding affinity between the molecules in the
Steps includes: complex.

Table 1. Difference between rational drug design and computer aided drug design

Rational Drug Design Computer Aided Drug Design

1. It is Time consuming Method. 1. It is Time saving Method
2. It is very slow Process and less Accuracy. 2. It is very Rapid Process and More Accuracy.
3. It is costly process. 3. It is cost effective process.
4. It required More manpower. 4. It Required Less manpower
5. In this Finding New medication Based On 5. In this Finding New Medication Based on
knowledge of Biological Target. Structure and Ligand based.
6. It is not used for Drug repurposing. 6. It is Useful for Drug Repurposing.
7. Ligand d Receptor Interaction is not evaluated. 7. Ligand receptor Interaction is Evaluated.
8. It is not helpful for the Rapid designing and 8. It is helpful for the Rapid designing and
discovery of New Therapeutic Entity. discovery of New Therapeutic Entity.
9. In this Do not need to know the Biological 9. In this need to know the Biological target
target structure. structure.

48
 Bhagat et al.; JPRI, 33(30B): 46-58, 2021;; Article no.JPRI.68704
no.

Dipole Induced
Dipole
ELECTROSTA Charge Induced
TIC FORCES Dipole
Charge Induced
Charge
ELECTRODYNA Vanders wall
DIFFERENT MIC interaction
TYPES OF
FORCES
Caused by
STERIC
entropy

Hydrogen bond
SOLVENT
RELATED Hydrophobic
interaction
Fig. 3. Interactions different types

5. TYPES OF MOLECULAR DOCKING a) Knowledge-based

based scoring function uses
the statistics of the observed inter-atomic
inter
1 Search Algorithm: The experimentation contact frequencies in a large database of
method determines the binding modes and the crystal structure of protein-ligand
protein
number of configurations creates. For docking complexes. Molecular interactions close to
analysis, the Monte Carlo method, fragment and the maximum frequency of interactions in
genetic based, systemic searches is applied. the data-base
base will have a high binding
affinity [80-85].. A molecular interaction with
a. Rigid Docking a low binding affinity in data base will have
b. Flexible Docking a low frequency of interaction.
2. Rigid Docking: In this docking the receptor b) Energy component scoring method is
and ligand molecule both are fixed. Docking is based on the mathematical assumption
performed. that change in free energy upon binding of
a ligand to a protein
rotein target (DG bind) is the
3. Flexible Docking: In this docking the ligand
sum of the free energy for ligand-protein
ligand
and the receptor both are movable. It is
interaction, ligand-protein
protein and solvent
conformationally flexible. Each rotation the
interaction, conformational changes in the
energy is calculated. Each conformation
mation surface
ligand and protein and the motion in the
cell occupancy is calculated. After that the most
ligand and protein target during complex
optimum binding pose is selected.
formation [86-90].
4. Scoring Function: The binding affinity is
directly corresponding to the binding score. The 6. MOLECULAR DOCKING MECHANICS
best binders are best scoring ligands. It can be STEPS
experimental, knowledge and molecular
mechanics based. Docking Scoring is play In In-Silico
Silico method studied the intermolecular
important role in designing of drug: interaction between 2 drug molecules. The
protein receptor is Macromolecule. It acted as an
a) Knowledge-based and inhibitor. The following steps involved in docking
b) Energy component methods process are as.

49
 Bhagat et al.; JPRI, 33(30B): 46-58, 2021;; Article no.JPRI.68704
no.

Step I – Preparation of protein and Ligand: due to drug likeness properties for
From Research Collaboratory Structural molecules.
Bioinformatics Protein data bank (PDB)
downloading the 3D-structure
structure of the Step III- Grid Generation: In this all factors like
Protein. After that downloaded structure site, rotatable group, excluded volumes,
should be pre-processed.
processed. From the cavity constraints kept constant. The num
number of genetic
removal of the water molecules, the operations performed (crossover, migration,
charges stabilization, missing residues mutation) is the key parameter in determining.
filling, add hydrogen atom side chains Binding Cavity Prediction are to be done.
generation.
Step IV –Prediction
Prediction of Active site: The active
Step II –Ligand Preparation: By using different site of protein molecule should be predicted. after
databases such as ZINC, Pub b Chem Ligands that Preparation
paration of protein, the water molecules
molecule can be downloaded. It can be draw in and hetero atoms if present they are removed
Chem sketch tool in mol file. Then utilized from cavity.
LIPINSKY’S RULE OF 5 for this ligand
molecule. It is used for the drug like and Step V- Docking: Ligand and protein
unlike molecules. It increases the high interactions are analyzed. Best docking score
chance of success rate and decrease the failure should be selected.

1. RIGID OR LOCK AND KEY

TYPES OF
MOLECULAR
DOCKING 2. FLEXIBLE OR
INDUCED FIT
Fig. 4. Types of molecular docking

Fig. 5. Flexible Docking

Step I- Protein
Prepration
Step II- Prepration of
ligand
Step III-Grid
Generation
Step IV-Active site
prediction
Step 4- Docking

Fig. 6. Molecular docking mechanics steps

50
 Bhagat et al.; JPRI, 33(30B): 46-58, 2021;; Article no.JPRI.68704
no.

Table 2. Difference between lipinsky’s rule and muegge rule

Properties Lipinsky’s rule of 5 Muegge RULE

Molecular weight < 500 g/mol 780.94 g/mol
Log P <5 3.92
H- bond donor <5 6
H- bond acceptor < 10 14
Polar surface area < 140 A0 203.06 A0

Fig. 7. Drug receptor response

Hit
Identification
(Virtual Lead
Protein Screening) Optimizatio
engineering n (Drug
discovery)
Enzymatic
reactions Bioremedia
Mechanisms tion

Applications of
Structure –
function Molecular Biological
Studies Docking activity
Prediction
for protein
targets Prediction
Searching
lead of binding
structures Protein – site
De-
Protein/ Nucleic
orphaning
acid
of protein
interactions

Fig. 8. Application of molecular docking

51
 Bhagat et al.; JPRI, 33(30B): 46-58, 2021; Article no.JPRI.68704

Table 3. Docking software

Sr Program Docking Scoring Advantages Disadvantages Licence

No. Approach Function Term
1. Auto Genetic force-field Small cavities Polar flexible Free for
Dock algorithm methods opened for ligand Academic
and hydrophobic Use
Simulated ligands
Annealing
2. Dock fitting of Chem Known binding Slow speed Free for
Shape Score site Academic
Use
3. Flex X Construction Flex X Small cavities More flexible Commercial
Increment Score, opened for ligands Free
hydrophobic evaluation
ligands (6week)
4. FRED fitting of Piece wise High speed, Polar ligands Free for
Shape Linear large binding Academic
Potential, site Use
5. Glide Sampling of Glide Flexible Ranking very Commercial
Monte Carlo Score, Hydrophobic slow
Glide ligands
Comp
6. GOLD GA Gold and Small Large cavity Commercial
searching Chem Hydrophobic ligand ranking
Score ligands
7. Ligand Fit Sampling Ligand Known binding Slow speed Commercial
Monte Carlo Score site

7. DISCUSSION AND CONCLUSION discovery. Malaria, Heart failure, Cancer and

other infectious diseases are public health
Molecular Docking provides different tools used challenges in most countries due to the
for drug design and discovery. The medicinal emergence of drug resistance strains, thus
chemist easy to visualization of molecules necessitating the need for novel effective
structural databases. It successfully predicts the remedies. Identification of new indication from
binding of ligands within receptor. These drugs existing drug and application newly identified
make molecular docking process in drug design. drug to treatment of disease. Computational drug
It is time-saving, cost-effective. It is used for the design, a cost- effective and less time-consuming
novel drug development [91-95]. It Is Very Useful approach, is a validated and reliable alternative
for Future Medicinal Chemist to Discover the to the cost expensive and time-consuming
Novel Drug Design and Novel Drug Development conventional method of drug discovery. It is
Process. Molecular docking method complication become powerful alternative strategy to discover
is optimization of lead molecule, biological and develop novel drugs from existing drug with
pathway evaluation and de Novo drug design. In the help of Computer Aided Drug Design
this review mention all information regarding (CADD).
molecular docking. Malaria, Heart failure, Cancer
and other infectious diseases are public health CONSENT
challenges in most countries due to the
emergence of drug resistance strains, thus It is not applicable.
necessitating the need for novel effective
ETHICAL APPROVAL
remedies [96-100]. Identification of new
indication from existing drug and application It is not applicable.
newly identified drug to treatment of disease.
Computational drug design, a cost- effective and ACKNOWLEDGEMENT
less time-consuming approach, is a validated
and reliable alternative to the cost expensive and RB thanks to the Head of the Pharmaceutical
time-consuming conventional method of drug chemistry school of pharmacy, SRTMU Nanded

52
 Bhagat et al.; JPRI, 33(30B): 46-58, 2021; Article no.JPRI.68704

for their guidance for making manuscript. I would Model. 2003;21(5):463–

like to special thanks Datta Meghe College of 472. [PubMed] [Google Scholar]
Pharmacy, Datta Meghe Institute of Medical 10. Fischer E. Einfluss der configuration auf
Sciences (Deemed to be University) Salod (H) die wirkung derenzyme. Ber. Dt. Chem.
Wardha for financial support. Ges. 1894;27:2985–2993. [Google
Scholar]
COMPETING INTERESTS 11. Koshland DE Jr. Correlation of structure
and function in enzyme action. Science.
Authors have declared that no competing 1963;142:1533–1541. [PubMed] [Google
interests exist. Scholar]
12. Hammes GG. Multiple conformational
REFERANCES
changes in enzyme catalysis.
Biochemistry. 2002;41(26):8221–8228.
1. Jorgensen WL. The many roles of [PubMed] [Google Scholar]
computation in drug
discovery. Science. 2004;303(5665):1813– 13. Rarey M, Kramer B, Lengauer T, Klebe G.
1818. [PubMed] [Google Scholar] A fast flexible docking method using an
incremental construction algorithm. J Mol
2. Bajorath J. Integration of virtual and high- Biol. 1996;261(3):470–489. [PubMed]
throughput screening. Nat Rev Drug [Google Scholar]
Discov. 2002;1(11):882–
894. [PubMed] [Google Scholar] 14. Morris GM, Goodsell DS, Halliday RS,
Huey R, Hart WE, Belew RK, Olson AJ.
3. Walters WP, Stahl MT, Murcko MA. Virtual Automated docking using a Lamarckian
screening - an overview. Drug Discov. genetic algorithm and an empirical binding
Today. 1998;3:160–178. [Google Scholar] free energy function. Journal of
4. Langer T, Hoffmann RD. Virtual screening: Computational
An effective tool for lead structure Chemistry. 1998;19(14):1639–
discovery? Curr Pharm 1662. [Google Scholar]
Des. 2001;7(7):509– 15. Jones G, Willett P, Glen RC, Leach AR,
527. [PubMed] [Google Scholar] Taylor R. Development and validation of a
5. Kitchen DB, Decornez H, Furr JR, Bajorath genetic algorithm for flexible docking. J Mol
J. Docking and scoring in virtual screening Biol. 1997;267(3):727–
for drug discovery: Methods and 748. [PubMed] [Google Scholar]
applications. Nat Rev Drug 16. Friesner RA, Banks JL, Murphy RB,
Discov. 2004;3(11):935– Halgren TA, Klicic JJ, Mainz DT, Repasky
949. [PubMed] [Google Scholar] MP, Knoll EH, Shelley M, Perry JK, Shaw
6. Gohlke H, Klebe G. Approaches to the DE, Francis P, Shenkin PS. Glide: a new
description and prediction of the binding approach for rapid, accurate docking and
affinity of small-molecule ligands to scoring. 1 Method and assessment of
macromolecular receptors. Angew Chem docking accuracy. J Med
Int Ed Engl. 2002;41(15):2644– Chem. 2004;47(7):1739–
2676. [PubMed] [Google Scholar] 1749. [PubMed] [Google Scholar]
7. Moitessier N, Englebienne P, Lee D, 17. McGann MR, Almond HR, Nicholls A,
Lawandi J, Corbeil CR. Towards the Grant JA, Brown FK. Gaussian docking
development of universal, fast and highly functions. Biopolymers. 2003;68(1):76–
accurate docking/scoring methods: a long 90. [PubMed] [Google Scholar]
way to go. Br J Pharmacol. 18. Shoichet BK, McGovern SL, Wei B, Irwin
2008;153(Suppl 1):S7–26. [PMC free JJ. Hits, leads and artifacts from virtual and
article] [PubMed] [Google Scholar] high throughput screening. Molecular
8. Brady GP Jr, Stouten PF. Fast prediction Informatics: Confronting Complexity;
and visualization of protein binding pockets 2002. [Google Scholar]
with PASS. J Comput Aided Mol 19. Bailey D, Brown D. High-throughput
Des. 2000;14(4):383– chemistry and structure-based design:
401. [PubMed] [Google Scholar] Survival of the smartest. Drug Discov
9. Mezei M. A new method for mapping Today. 2001;6(2):57–
macromolecular topography. J Mol Graph 59. [PubMed] [Google Scholar]

53
 Bhagat et al.; JPRI, 33(30B): 46-58, 2021; Article no.JPRI.68704

20. Kuntz ID, Blaney JM, Oatley SJ, Langridge 30. Jiang F, Kim SH. “Soft docking”: matching
R, Ferrin TE. A geometric approach to of molecular surface cubes. J Mol
macromolecule-ligand interactions. J Mol Biol. 1991;219(1):79–
Biol. 1982;161(2):269– 102. [PubMed] [Google Scholar]
288. [PubMed] [Google Scholar] 31. Claussen H, Buning C, Rarey M, Lengauer
21. Halperin I, Ma B, Wolfson H, Nussinov R. T. FlexE: Efficient molecular docking
Principles of docking: An overview of considering protein structure variations. J
search algorithms and a guide to scoring Mol Biol. 2001;308(2):377–
functions. Proteins. 2002;47(4):409– 395. [PubMed] [Google Scholar]
443. [PubMed] [Google Scholar] 32. Alonso H, Bliznyuk AA, Gready JE.
22. Coupez B, Lewis RA. Docking and scoring- Combining docking and molecular dynamic
-theoretically easy, practically simulations in drug design. Med Res
impossible? Curr Med Rev. 2006;26(5):531–
Chem. 2006;13(25):2995– 568. [PubMed] [Google Scholar]
3003. [PubMed] [Google Scholar] 33. Sander T, Liljefors T, Balle T. Prediction of
23. Kontoyianni M, Madhav P, Suchanek E, the receptor conformation for iGluR2
Seibel W. Theoretical and practical agonist binding: QM/MM docking to an
considerations in virtual screening: A extensive conformational ensemble
beaten field? Curr Med generated using normal mode analysis. J
Chem. 2008;15(2):107– Mol Graph Model. 2008;26(8):
116. [PubMed] [Google Scholar] 1259–1268.
24. Brooijmans N, Kuntz ID. Molecular [PubMed][Google Scholar]
recognition and docking algorithms. Annu 34. Subramanian J, Sharma S, BR C. A novel
Rev Biophys Biomol Struct. 2003;32:335– computational analysis of ligand-induced
373. [PubMed] [Google Scholar] conformational changes in the ATP binding
25. ten Brink T, Exner TE. Influence of sites of cyclin dependent kinases. J Med
protonation, tautomeric, and Chem. 2006;49(18):5434–
stereoisomeric states on protein-ligand 5441. [PubMed] [Google Scholar]
docking results. J Chem Inf 35. Subramanian J, Sharma S, BR C.
Model. 2009;49(6):1535– Modeling and selection of flexible proteins
1546. [PubMed] [Google Scholar] for structure-based drug design: backbone
26. Cross JB, Thompson DC, Rai BK, Baber and side chain movements in p38
JC, Fan KY, Hu Y, Humblet C. Comparison MAPK. ChemMedChem. 2008;3(2):336–
of several molecular docking programs: 344. [PubMed] [Google Scholar]
pose prediction and virtual screening 36. R, Ginalski K. Can we trust docking
accuracy. J Chem Inf results? Evaluation of seven commonly
Model. 2009;49(6):1455– used programs on PDBbind database. J
1474. [PubMed] [Google Scholar] Comput Chem; 2010.
27. Li X, Li Y, Cheng T, Liu Z, Wang R. DOI: 10.1002/jcc.21643. [PubMed] [Google
Evaluation of the performance of four Scholar]
molecular docking programs on a diverse 37. McConkey BJ, Sobolev V, Edelman M.
set of protein-ligand complexes. J Comput The performance of current methods in
Chem. 2010;31(11):2109– ligand-protein docking. Current
2125. [PubMed] [Google Scholar] Science. 2002;83:845–855. [Google
28. Perola E, Walters WP, Charifson PS. A Scholar]
detailed comparison of current docking and 38. Goodford PJ. A computational procedure
scoring methods on systems of for determining energetically favorable
pharmaceutical binding sites on biologically
relevance. Proteins. 2004;56(2):235– important macromolecules. J Med
249. [PubMed] [Google Scholar] Chem. 1985;28(7):849–857.
29. Sherman W, Day T, Jacobson MP, [PubMed] [Google Scholar]
Friesner RA, Farid R. Novel procedure for 39. Kastenholz MA, Pastor M, Cruciani G,
modeling ligand/receptor induced fit Haaksma EE, Fox T. GRID/CPCA: A new
effects. J Med Chem. 2006;49(2):534– computational tool to design selective
553. [PubMed] [Google Scholar]

54
 Bhagat et al.; JPRI, 33(30B): 46-58, 2021; Article no.JPRI.68704

ligands. J Med Chem. 2000;43(16):3033– inhibitor leads. J Comput Aided Mol

3044. Des. 1992;6(6):593–606.
[PubMed] [Google Scholar] [PubMed] [Google Scholar]
40. Levitt DG, Banaszak LJ. Pocket: A 50. Goodsell DS, Lauble H, Stout CD, Olson
computer graphics method for identifying AJ. Automated docking in crystallography:
and displaying protein cavities and their Analysis of the substrates of aconitase.
surrounding amino acids. J Mol Proteins. 1993;17(1):1–10.
Graph. 1992;10(4):229–234.
[PubMed] [Google Scholar]
[PubMed] [Google Scholar]
51. Hart TN, Read RJ. A multiple-start monte
41. Laskowski RA. Surfnet: A program for
carlo docking method. Proteins.
visualizing molecular surfaces, cavities,
1992;13(3):206–222.
and intermolecular interactions. J Mol
Graph. 1995;13(5):323–330. 307–328. [PubMed] [Google Scholar]
[PubMed] [Google Scholar] 52. Goodsell DS, Olson AJ. Automated
42. Glaser F, Morris RJ, Najmanovich RJ, docking of substrates to proteins by
Laskowski RA, Thornton JM. A method for simulated
localizing ligand binding pockets in protein annealing. Proteins. 1990;8(3):195–
structures. Proteins. 2006;62(2): 202. [PubMed] [Google Scholar]
479–488. [PubMed] [Google Scholar] 53. Abagyan R, Totrov M, Kuznetsov D. ICM-A
43. Ewing TJ, Makino S, Skillman AG, Kuntz new method for protein modeling and
ID. DOCK 4.0: Search strategies for design: Applications to docking and
automated molecular docking of flexible structure prediction from the distorted
molecule databases. J Comput Aided Mol native conformation. J. Comput.
Des. 2001;15(5):411– Chem. 1994;15:488–506. [Google Scholar]
428. [PubMed] [Google Scholar] 54. McMartin C, Bohacek RS. QXP: Powerful,
44. Welch W, Ruppert J, Jain AN. rapid computer algorithms for structure-
Hammerhead: fast, fully automated based drug design. J Comput Aided Mol
docking of flexible ligands to protein Des. 1997;11(4):333–344.
binding sites. Chem Biol. 1996;3(6):449– [PubMed] [Google Scholar]
462. [PubMed] [Google Scholar] 55. Accelrys Inc., San Diego, CA, USA.
45. Schnecke V, Kuhn LA. Virtual screening 56. Oshiro CM, Kuntz ID, Dixon JS. Flexible
with solvation and ligand-induced ligand docking using a genetic algorithm. J
complementarity. Perspectives in Drug Comput Aided Mol Des. 1995;9(2):113–
Discovery and Design. 2000;20:171– 130. [PubMed] [Google Scholar]
190. [Google Scholar] 57. Verdonk ML, Cole JC, Hartshorn MJ,
46. Zsoldos Z, Reid D, Simon A, Sadjad BS, Murray CW, Taylor RD. Improved protein-
Johnson AP. eHiTS: An innovative ligand docking using
approach to the docking and scoring gold. Proteins. 2003;52(4):609–623.
function problems. Curr Protein Pept [PubMed] [Google Scholar]
Sci. 2006;7(5):421–435. [PubMed] [Google
58. Brint AT, Willett P. Algorithms for the
Scholar]
Identification of three-dimensional maximal
47. Miranker A, Karplus M. Functionality maps common substructures. J. Chem. Inf.
of binding sites: A multiple Comput. Sci. 1987;27:152–158. [Google
copy simultaneous search Scholar]
method. Proteins. 1991;11(1):29–34.
59. Fischer D, Norel R, Wolfson H, Nussinov
[PubMed] [Google Scholar] R. Surface motifs by a computer vision
48. Eisen MB, Wiley DC, Karplus M, Hubbard technique: Searches, detection, and
RE. HOOK: A program for finding novel implications for protein-ligand
molecular architectures that satisfy the recognition. Proteins. 1993;16(3):278–
chemical and steric requirements of a 292. [PubMed] [Google Scholar]
macromolecule binding 60. Norel R, Fischer D, Wolfson HJ, Nussinov
site. Proteins. 1994;19(3):199–221. R. Molecular surface recognition by a
[PubMed] [Google Scholar] computer vision-based technique. Protein
49. Bohm HJ. LUDI: Rule-based automatic Eng. 1994;7(1):39–46. [PubMed] [Google
design of new substituents for enzyme Scholar]

55
 Bhagat et al.; JPRI, 33(30B): 46-58, 2021; Article no.JPRI.68704

61. Miller MD, Kearsley SK, Underwood DJ, 71. Briggs JM, Marrone TJ, McCammon JA.
Sheridan RP. FLOG: A system to select Computational science new horizons and
‘quasi-flexible’ ligands complementary to a relevance to pharmaceutical
receptor of known three-dimensional design. Trends Cardiovasc.
structure. J Comput Aided Mol Med. 1996;6:198–206. [PubMed] [Google
Des. 1994;8(2):153– Scholar]
174. [PubMed] [Google Scholar] 72. Bohm HJ. Prediction of binding constants
62. Diller DJ, Merz KM., Jr. High throughput of protein ligands: a fast method for the
docking for library design and library prioritization of hits obtained from design or
prioritization. Proteins. 2001;43(2):113– 3D database search programs. J Comput
124. [PubMed] [Google Scholar] Aided Mol Des. 1998;12(4):309–
63. Burkhard P, Taylor P, Walkinshaw MD. An 323. [PubMed] [Google Scholar]
example of a protein ligand found by 73. Gehlhaar DK, Verkhivker GM, Rejto PA,
database mining: Description of the Sherman CJ, Fogel DB, Fogel LJ, Freer
docking method and its verification by a ST. Molecular recognition of the
2.3 A X-ray structure of a thrombin-ligand inhibitor AG-1343 by HIV-1 protease:
complex. J Mol Biol. 1998;277(2): Conformationally flexible docking
449–466. by evolutionary programming. Chem
[PubMed][Google Scholar] Biol. 1995;2(5):317–
64. DesJarlais RL, Sheridan RP, Dixon JS, 324. [PubMed] [Google Scholar]
Kuntz ID, Venkataraghavan R. Docking 74. Verkhivker GM, Bouzida D, Gehlhaar DK,
flexible ligands to macromolecular Rejto PA, Arthurs S, Colson AB, Freer ST,
receptors by molecular shape. J Med Larson V, Luty BA, Marrone T, Rose PW.
Chem. 1986;29(11):2149– Deciphering common failures in molecular
2153. [PubMed] [Google Scholar] docking of ligand-protein complexes. J
65. Kuntz ID, Leach AR. Conformational Comput Aided Mol Des. 2000;14(8):731–
analysis of flexible ligands in 751. [PubMed] [Google Scholar]
macromolecular receptor sites. J. Comput. 75. Clark KP. Ajay, Flexible ligand docking
Chem. 1992;13:730–748. [Google Scholar] without parameter adjustment across four
66. Kollman PA. Free energy calculations: ligand- receptor complexes. J Comput
Applications to chemical and biochemical Chem. 1995;16:1210–1226. [Google
phenomena. Chem. Rev. 1993;93:2395– Scholar]
2417. [Google Scholar] 76. Taylor JS, Burnett RM. DARWIN: A
67. Aqvist J, Luzhkov VB, Brandsdal BO. program for docking flexible
Ligand binding affinities from MD molecules. Proteins. 2000;41(2):173–
simulations. Acc Chem 191. [PubMed] [Google Scholar]
Res. 2002;35(6):358– 77. Cornell WD, Cieplak P, Bayly CI, Gould IR,
365. [PubMed] [Google Scholar] Merz KM, Ferguson DM, Spellmeyer DC,
68. Carlson HA, Jorgensen WL. An extended Fox T, Caldwell JW, Kollman PA. A second
linear response method for determining generation force field for the simulation of
free energies of hydration. J Phys proteins, nucleic acids, and
Chem. 1995;99:10667–10673. [Google organic molecules. J. Am. Chem.
Scholar] Soc. 1995;117:5179–5197. [Google
Scholar]
69. Shoichet BK, Stroud RM, Santi DV, Kuntz
ID, Perry KM. Structure-based discovery of 78. Weiner SJ, Kollman PA, Case DA, Singh
inhibitors of thymidylate UC, Ghio C, Alagona G, Profeta S, Jr.,
synthase. Science. 1993;259(5100):1445– Weiner P. New force field for molecular
1450. [PubMed] [Google Scholar] mechanical simulation of nucleic acids and
proteins. J. Am. Chem.
70. Michel J, Verdonk ML, Essex JW. Protein- Soc. 1984;106:765–784. [Google Scholar]
ligand binding affinity predictions by
implicit solvent simulations: a tool 79. Brooks BR, Bruccoleri RE, Olafson BD,
for lead optimization? J Med Chem. States DJ, Swaminathan S, Karplus M.
2006;49(25):7427–7439. CHARMM: A program for macromolecular
energy, minimization, and
[PubMed] [Google Scholar]

56
 Bhagat et al.; JPRI, 33(30B): 46-58, 2021; Article no.JPRI.68704

dynamics calculations. J. Comput. novo design of enzyme inhibitors by Monte

Chem. 1983;4:187–217. [Google Scholar] Carlo ligand generation. J Med
80. Srinivasan J, Cheatham TE, Cieplak P, Chem. 1995;38(3):466–
Kollman PA, Case DA. Continuum solvent 472. [PubMed] [Google Scholar]
studies of the stability of DNA, RNA, and 89. Eldridge MD, Murray CW, Auton TR,
phosphoramidateâ^’DNA Helices. Journal Paolini GV, Mee RP. Empirical scoring
of the American Chemical functions: I. The development of a fast
Society. 1998;120(37):9401–9409. [Google empirical scoring function to estimate the
Scholar] binding affinity of ligands in receptor
81. Kollman PA, Massova I, Reyes C, Kuhn B, complexes. J Comput Aided Mol
Huo S, Chong L, et al. 3rd calculating Des. 1997;11(5):425–
structures and free energies of complex 445. [PubMed] [Google Scholar]
molecules: Combining molecular 90. Muegge I, Martin YC. A general and fast
mechanics and continuum models. Acc scoring function for protein-ligand
Chem Res. 2000;33(12):889– interactions: A simplified potential
897. [PubMed] [Google Scholar] approach. J Med Chem. 1999;42(5):791–
82. Still WC, Tempczyk A, Hawley RC, 804. [PubMed] [Google Scholar]
Hendrickson T. Semianalytical treatment of 91. Mitchell JBO, Laskowski RA, Alex A,
solvation for molecular mechanics and Thornton JM. Bleep-potential of mean
dynamics. J. Am. Chem. Soc. force describing protein-ligand interactions:
1990;112(16):6127–6129. [Google I. generating potential. J. Comput.
Scholar] Chem. 1999;20(11):1165–1176. [Google
83. Guimaraes CR, Mathiowetz AM. Scholar]
Addressing limitations with the MM-GB/SA 92. Ishchenko AV, Shakhnovich EI. SMall
scoring procedure using the WaterMap Molecule Growth 2001 (SMoG2001): An
method and free energy perturbation improved knowledge-based scoring
calculations. J Chem Inf Model. 50(4):547– function for protein-ligand interactions. J
559. [PubMed] [Google Scholar] Med Chem. 2002;45(13):2770–
84. Singh N, Warshel A. Absolute binding free 2780. [PubMed] [Google Scholar]
energy calculations: On the accuracy of 93. Feher M, Deretey E, Roy S. BHB: A simple
computational scoring of protein-ligand knowledge-based scoring function to
interactions. Proteins. 2010;78(7):1705– improve the efficiency of database
1723. [PMC free article] [PubMed] [Google screening. J Chem Inf Comput
Scholar] Sci. 2003;43(4):1316–
85. Gabb HA, Jackson RM, Sternberg MJ. 1327. [PubMed] [Google Scholar]
Modelling protein docking using shape 94. Verkhivker G, Appelt K, Freer ST,
complementarity, electrostatics and Villafranca JE. Empirical free
biochemical information. J Mol Biol. energy calculations of ligand-protein
1997;272(1):106–120. [PubMed] [Google crystallographic complexes. I. Knowledge-
Scholar] based ligand-protein interaction potentials
86. Jain AN. Scoring noncovalent protein- applied to the prediction of human
ligand interactions: a continuous immunodeficiency virus 1 protease
differentiable function tuned to compute binding affinity. Protein Eng.
binding affinities. J Comput Aided Mol 1995;8(7):677–691. [PubMed] [Google
Des. 1996;10(5):427– Scholar]
440. [PubMed] [Google Scholar] 95. Wallqvist A, Jernigan RL, Covell
87. Head RD, Smythe ML, Oprea TI, Waller DG. A preference-based free-energy
CL, Green SM, Marshall GR. VALIDATE: A parameterization of enzyme-inhibitor
new method for the receptor-based binding. Applications to HIV-1-protease
prediction of binding affinities of inhibitor design. Protein Sci.
novel ligands. J. Am. Chem. 1995;4(9):1881–1903. [PMC free article]
Soc. 1996;118:3959–3969. [Google [PubMed] [Google Scholar]
Scholar] 96. Gohlke H, Hendlich M, Klebe G.
88. Gehlhaar DK, Moerder KE, Zichi D, Knowledge-based scoring function to
Sherman CJ, Ogden RC, Freer ST. De predict protein-ligand interactions. J Mol

57
 Bhagat et al.; JPRI, 33(30B): 46-58, 2021; Article no.JPRI.68704

Biol. 2000;295(2):337–356. [PubMed] dimensional structures into proteins. J Med

[Google Scholar] Chem. 1999;42(25):5100–
97. DeWitte RS, Shakhnovich EI. SMoG: de 5109. [PubMed] [Google Scholar]
Novo Design Method Based on Simple, 99. Feher M. Consensus scoring for protein-
Fast, and Accurate Free Energy Estimates. ligand interactions. Drug Discov
1 Methodology and Supporting Evidence. Today. 2006;11(9-10):421–
J. Am. Chem. Soc. 1996;118:11733– 428. [PubMed] [Google Scholar]
11744. [Google Scholar] 100. Clark RD, Strizhev A, Leonard JM, Blake
98. Charifson PS, Corkery JJ, Murcko MA, JF, Matthew JB. Consensus scoring for
Walters WP. Consensus scoring: A ligand/protein interactions. J Mol Graph
method for obtaining improved hit rates Model. 2002;20(4):281–
from docking databases of three- 295. [PubMed] [Google Scholar]

© 2021 Bhagat et al.;This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

Peer-review history:
The peer review history for this paper can be accessed here:
http://www.sdiarticle4.com/review-history/68704

58

View publication stats