People will know about the Computer Aided Drug Design Of M.pharm Chemistry

1. TOPIC:- CONFORMATIONAL SEARCH USED IN
PHARMACOPHORE MAPPING
PRESENTED BY
NABAJYOTI KALITA
M.PHARM 2nd Sem (Pharm Chemistry)
Dept. of Pharmaceutical Sciences,
Dibrugarh University,2023.
COMPUTER AIDED DRUG DESIGN
(MPC 203T)

2. INTRODUCTION
Pharmacophore- first introduced in1990 by Paul
Henrich. It is an abstract decription of molecule
features icluding 3D( hydrophobic groups,
hydrogen bond donor/ acceptor), 2D(
substructures), 1D( physical or biological) which
are necessary for molecular recognition of a
ligand by a biological macromolecule.
Pharmacophore mapping- it is the definition and
placement of pharmacophoric features and the
alignment techniques used to overlay 3D and the
process of deriving pharmacophore.

3. Continued…..
It consist of three steps
Identifying common binding element that are
responsible for biological activity
Generation of potential conformations that
active compound may adopt
Determine the 3D relationship between
pharmacophore element in each conformation
generated

4. CONFORMATION
Conformation generally means structural
arrangement
Conformations are different three dimensional
structures of molecules that arise from-
 Rotation about single bond (torsion angles)
 Different ring conformation
The biological activity of molecules is strongly
dependent on their conformation
Having several double bonds results in a
“combinatorial explosion”

5. Two approaches to handling conformational
flexibility
CONFORMATION SELECTION EXPLORATION OF CONFORMATIONAL
SPACE
When a new molecule is to be
registered in a database, a
conformational analysis is used to
select diverse conformers spanning the
low energy conformational space
Use of triangle smoothing to identify
min-max distance between each atom-
pair
Each such conformer is loaded into the
database and then searched as if it
was a single, rigid structure
Creation of distance range graph for
each distance structure
Trade off between effectiveness of
coverage and efficiency of searching
Screen and graph search of the min-
max distance data using appropriately
modified algorithm

6. Different methods
The conformation search can be quite large and can
be approaches using following methods
1. Systemic search method
2. Distance geometry method
3. Clique detection algorithm

7. SYSTEMIC SEARCH METHOD
 Simplest and deterministic
 Generates sterically allowed molecular
conformations by systematically varying sets of
specified torsion angles
 It allows to search for ring system conformations
and to specify the removal of duplicates from
resulting conformations based on energy and
geometry root mean square
 The pharmacophore type of systemic search
allows to produce sets of conformations that
share one or more common pharmacophores
over a series of molecules

9. Distance geometry method
Randomly samples conformations and are
particularly powerful for problems dealing
with molecular matching and flexibility
Used by Rubicon
Used to simultaneously device a set of
conformation with a previously defined set of
pharmacophoric groups overlaid
Special feature: conformational spaces of all
the molecules are considered simultaneously

12. CLIQUE DETECTION ALGORITHM
 Searches common sets of inter feature distances
within the group of active molecules
Tolerance of distances matches account for the
use of discrete conformations
Used by Disco Tech
When many Pharmacophoric groups are present
in the molecule it may be vary
Difficult to identify all possible conformations of
the functional groups
Clique defined as a “maximal completely
connected graph”

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