Receptor Mapping,
Pharmacophore Mapping and
Bioactive conformations
• In biochemistry a receptor is a protein molecule that recognises and
responds to endogenous chemical signals and responds to its
endogen ous ligands.
• However sometimes in pharmacology the term is also used to include
other proteins that are drug targets such as enzymes transpoters and
ion channels.
• Each receptor will bind only with the ligands of a particular structure
and activates or inhibits the pathway associated with it.
• Ligand binding is an equilibrium process
• One measure of how well a molecule fits a receptor is its binding
affinity, which is inversely related to the dissociation constant Kd.
• A good fit corresponds with high affinity and low Kd.
• UTILITY
• Depending on the type of information available two distinct
strategies may be employed in drug design:
• (1) Receptor mapping
• If an explicit structure of the drug receptor target is not available but
several competitive ligands that bind to the receptor are known the
receptor structure may be inferred based on what binds to it.
• (2) Receptor fitting
An explicit 3D structure is available from crystallographic or NMR
determination or from homology modeling
(a) De novo design of a structurally novel ligand
(b) The refinement of the existing lead
In receptor fitting, careful examination of the structure may
suggest ways in which the ligand can be modified to
enhance affinity.
Receptor fitting is used to yield many synthetic ideas or
database hits and these ideas need to be prioritized for
synthesis or screening.
It is also utilized in developing and employing accurate
methods for estimating the relative binding affinities of
candidate ligands.
BINDING SITE PROPERTIES
STEREOELECTRONIC FACTORS
•Ligand receptor complexes possess numerous
intermolecular hydrogen bonding contacts
•They usually bridge the protease-inhibitor and
antibody-antigen protein interfacial regions
•Amide groups in proteins and amino acid side-
chains account for almost all of the hydrogen bonds
seen between ligand and proteins.
• Non polar functional groups , not capable of hydrogen
bonding , can also contribute to specificity such as :
• (1) limonene and (2) carvone
• Limonene
• It is a chiral hydrocarbon
terpine devoid of H bonding
capability
• The mirror images of
limonene clearly interact
very differently with olfactor
receptors as the R(+)
enantiomer has a citrus
smell whereas the S(-)
enantiomeris harsh and
turpentine like.
• Carvone
• Here the (+) isomer has the fragrance of caraway
whereas the (-) isomer possesses the odour of spearmint
• Conformational flexibility and strain energy of the ligand
also play critical roles.
• A multiple regression analysis of the contributions of
various functional groups to binding demonstrates that, on
average each freely rotating bond in a ligand reduces
binding free energy by 0.7kcal/mol.
• Rigidification of a flexible ligand causes a substantial boost
in affinity
• Eg: H+/K+ ATPase inhibitor
The combined mapping of various receptors in each
receptor fingerprints
Pharmacophore Mapping is the definition and
placement of pharmacophoric features and the
alignment techniques used to overlay 3D.
Pharmacophore Mapping is the definition and placement of phar
macophoric features and the alignment techniques used to overla
y 3D.
Two somewhat distinct usages:
That substructure of a molecule that is responsible for its pharma
cological activity (c.f. chromophore)
A set of geometrical constraints between specific functional group
s
that enable the molecule to have biological activity
The process of deriving pharmacophore is known as pharmacophor
e mapping.
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It consist of three steps
(1) identifying common binding element that are responsible for
the biological activity;
(2) generating potential conformations that active compound ma
y adopt; and
(3) determining the 3D relationship between pharmacophore ele
ment in each conformation generated.
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The process of finding drug by design.
Based on what the drug targeting?
Metabolic or Signaling pathway Specific for di
sease or pathology.
Drugs
Bind to active site & Work.
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Usually pharmacophore based search are done in two steps.
First the software checks whether the compound has the atom typ
es or functional groups required by the pharmacophore,
than its checks whether the spatial arrangement of this element m
atches the query.
Flexible 3D searches identified a higher number of hits than rigid s
earches do.
However flexible searches are more time consuming than rigid
ones.
There are two main approaches for including conformational flexi
bility in to the search
one is top generate a user defined number of representative confo
rmation for each molecules when the database is to created,
the other is to generate conformation during the search.
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Pharmacophore model provide powerful filter tools for virtual scr
eening even in case where the protein structure is not available,
pharmacophore filter are much faster than docking approaches, a
nd there for greatly reduce the number of compound subjected to
the more expensive docking application.
Another interesting aspect of pharmacophore in virtual screening i
s 3D- pharmacophore diversity.
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What is a bioactive conformation? It is a conformation a molecule
must adopt to be recognized by a receptor and produce a biological
response. Predicting that conformations for flexible small molecules
is a challenging question in drug design.
Bioactive Conformational Ensemble (BCE) is a platform designed to
efficiently generate bioactive conformers and speed up the drug
discovery process. The server incorporates powerful methods of
conformational analysis that enable the prediction of bioactive
conformers for known and novel drugs.
Drug discovery and development is challenging, time consuming
and expensive. Computer-aided drug design (CADD) can be used to
increase the efficiency of the drug discovery process. One
fundamental goal in drug design is to predict whether a given
molecule will bind to a target and with which conformation.
Here we present the Bioactive Conformational Ensemble, a
comprehensive platform including a database system and an analysis
section, aimed to generate bioactive conformers. We used a
powerful multilevel strategy that combines low-level (LL) method
for sampling the conformational minima and high-level (HL) ab-
initio calculations for estimating their relative stability.
Bioactive Conformational Ensemble helps you to increase the
success of your conformational search of drug-like compounds in
solution and speed-up drug discovery process.
BIOACTIVE CONFORMATIONAL ENSEMBLE SERVER AND DATABASE. A
PUBLIC FRAMEWORK TO SPEED UP IN SILICO DRUG DISCOVERY
Sanja Zivanovic , Genís Bayarri, Francesco Colizzi, David Moreno, Josep Lluís Gelpí,
Robert Soliva, Adam Hospital and Modesto Orozco. J. Chem. Theory Comput. 2020
