The document discusses pharmacophore modeling, which involves identifying the 3D arrangement of functional groups necessary for a molecule to bind to a target site and trigger a biological response. It notes that pharmacophore modeling is important for understanding receptor-ligand interactions and for drug design. Two types are described: ligand-based, which extracts common chemical features from known ligands in the absence of the target structure, and structure-based, which generates features from the target or target-ligand complex structure. Pharmacophore models can be used for virtual screening to identify molecules that encode the required interaction pattern. The document also discusses the structure-activity relationship and notes that similar molecules do not always have similar activities, known as the SAR paradox.

1. Lecture 10- Pharmacophore Modeling and SAR paradox
BTT- 516– Drug Designing and Development

2. A pharmacophore is a specific 3D arrangement of functional groups within a
molecular framework that are necessary to bind to a macromolecule and/or an
enzyme active site
The identification of pharmacophore is important step in understanding the
interactions between a receptor and a ligand
Pharmacophore

3. Pharmacophore approaches are successful subfields of computer-aided drug
design (CADD) which have become one of the major tools in hit identification,
lead optimization, and rational design of novel drugs.
A pharmacophore model is the ensemble of common steric and electronic
features that are necessary to ensure the optimal molecular interactions with a
specific biological target and to trigger (or block) its biological response.
It can be used to represent and characterize molecules on schematic 2D or 3D
level by identifying the essential properties of molecular recognition. Every
type of atom or group in a compound can be reduced to a pharmacophore
feature (or pharmacophore fingerprints). These molecular patterns would be
labeled by several chemical properties, such as hydrogen bond donors or
acceptors, aromatic, cationic, etc, which can be used to analyze the similarity
among a library of small molecules and identify the key contributing features
to the biological function.
Pharmacophore Modeling

5. Ligand-based pharmacophore modeling
In the absence of the macromolecular target structure, ligand-based pharmacophore
modeling is an essential strategy for drug discovery.
In this method, the common chemical characteristics from 3D structures of multiple
known ligands are extracted through ligand alignment, which would represent the
essential interactions between ligand and potential macromolecular target.
Structure-based pharmacophore modeling
The structure-based pharmacophore modeling generates chemical features of the active
site and the sterical relationships from 3D structure of macromolecular target or
macromolecule-ligand complex. It probes the possible interaction sites between the
macromolecular target and the ligands.

6. Pharmacophore modeling is most often applied to virtual screening in order to identify
molecules triggering the desired biological effect.
For this purpose, researchers create a pharmacophore model (query) that most likely
encodes the correct 3D organization of the required interaction pattern.
Purpose of pharmacophore modeling
Why pharmacophore is important?
Pharmacophore is the essential to understand the interaction between the receptor and
ligand.
It is important feature to design new drug for treatment of the intended disease.
Pharmacophore defined as the essential geometric arrangement of atoms or functional
groups necessary to produce a given biological response.

8. Qing X, Lee XY, De Raeymaecker J, Tame JR, Zhang KY, De Maeyer M, Voet A.
Pharmacophore modeling: advances, limitations, and current utility in drug discovery.
Journal of Receptor, Ligand and Channel Research. 2014;7:81-92.

9. SAR paradox and concept of force field
The structure–activity relationship (SAR) is the relationship between the chemical
structure of a molecule and its biological activity.
Structure-Activity Relationship (SAR) is an approach designed to find relationships
between chemical structure (or structural-related properties) and biological activity (or
target property) of studied compounds.

10. The basic assumption for all molecule based hypotheses is that similar molecules have
similar activities. This principle is also called Structure-Activity Relationship (SAR).
The underlying problem is therefore how to define a small difference on a molecular
level, since each kind of activities
Examples: Reaction ability, Biotransformation ability, Solubility, target activity, and so
on, might depend on another difference. A good example was given in the bioisosterism
review of Patanie/LaVoie.
In general, one is more interested in finding strong trends. Created hypotheses usually
rely on a finite number of chemical data. Thus, the induction principle should be
respected to avoid overfitted hypotheses and deriving overfitted and useless
interpretations on structural/molecular data.
The SAR paradox refers to the fact that it is not the case that all similar molecules have
similar activities.

15. Thank you
Er. Rajan Rolta
Faculty of Applied Sciences and Biotechnology
Shoolini University,
Village Bhajol, Solan (H.P)
+91-7018792621 (Mob No.)
rajanrolta@shooliniuniversity.com