About Pharmacophore Mapping conformational search

1. Presented by
J O N J YOT I S A H A R I A H
M . P H A R M ( P H A R M . C H E M )
2 N D S E M E S T E R
Conformational Search Used
In Pharmacophore Mapping
Department of Pharmaceutical Sciences
Dibrugarh Univesity

2. PHARMACOPHORE
 A part of a molecular structure that is responsible for a
particular biological or pharmacological interaction that it
undergoes.
 First introduced in 1990 by “Paul Herilich”
 A pharmacophore is a representation of generalized
molecular features including;
 3D (hydrophobic groups, charged/ionizable groups, hydrogen bond
donors/acceptors)
 2D (substructures)
 1D (physical or biological)

3. PHARMACOPHORE MAPPING
 Pharmacophore Mapping is the definition and placement of
pharmacophoric features and the alignment techniques used to
overlay 3D.
 The process of deriving pharmacophore is known as pharmacophore
mapping.
 It consist of three steps
 (1) identifying common binding element that are responsible for the
biological activity;
 (2) generating potential conformations that active compound may
adopt; and
 (3) determining the 3D relationship between pharmacophore
element in each conformation generated

4. CONFORMATIONAL SEARCH
 Conformation generally means structural arrangement
 Conformations are different three-dimensional structures of molecules that
arise from :
 Rotation about single bonds (torsion angles)
 Different rings conformations
 The biological activity of molecules is strongly dependent on their
conformation
 Done by exploring the energy surface of a molecule and determining the
conformation with minimum energy
 Conformational analysis is needed to identify the ideal conformation of a
molecule
 If the torsion angles are incremented in steps of 30º, this means that a
molecule with 5 rotatable bonds with have 12^5 ≈ 250K conformations

5. TWO APPOACHES TO HANDLING
CONFORMATIONAL FLEXIBILITY
1. Conformer selection
 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.
 Each such conformer is loaded into the database and then
searched as if it was a single, rigid structure.
 Trade-off between effectiveness of coverage (selection of
many conformers) and efficiency of searching (selection of
few conformers).

6. TWO APPOACHES TO HANDLING
CONFORMATIONAL FLEXIBILITY
2. Exploration of conformational space
 Use of triangle smoothing to identify min-max distances
between each atom-pair.
 Creation of a distance-range (rather than a distance) graph
for each database structure.
 Screen and graph search of the min- max distance data using
appropriately modified algorithms.
 Final conformational analysis (by varying torsional angles)
of the hits resulting from the screen/graph searches.

7. DIFFERENT METHODS OF
CONFORMATIONAL SEARCH
Different methods
 Systematic search algorithms
 Model-building methods
 Random approaches – Generates conformers by random
perturbation of Cartesian coordinates or the torsion angles
of rotatable bonds
 Distance geometry – Determines the lower and upper
distances for all pairs of atoms in the molecule and the
distance matrix is generated
 Molecular dynamics

8. 1. Systematic search method
 Generates sterically allowed molecular conformations by
systematically varying sets of specified torsion angles
 The Systematic Search method allows to search for ring
system conformations and to specify the removal of
duplicates from the resulting conformations based on
energy and geometry root mean square comparisons
 The pharmacophore type of systematic search allows to
produce sets of conformations that share one or more
common pharmacophores, over a series of molecules

9. 1. Systematic search method
 Systematic search method
 Simplest
 Deterministic
 Advantages:
 A deterministic approach, hence a
systematic exploration of
conformational space
 Can be used for small molecules or
systems with 10-15 bonds

10. 1. Systematic search method

11. 2. Distance geometry method
 Randomly samples conformations and are particularly powerful
for problems dealing with molecular matching and flexibility
 Used by Rubicon
 Used to simultaneously derive a set of conformations with a
previously defined set of pharmacophoric groups overlaid
 Special Feature : conformational spaces of all the molecules are
considered simultaneously

12. 2. Distance geometry method

13. 2. Distance geometry method
Lower bounds for atoms that are in different molecules = zero
molecules can be overlaid in 3D space
Upper bounds for pairs of atoms that are in different molecules = large
value
Required to be superimposed in the pharmacophore

14. 3. Clique detection algorithm
 Searches common sets of inter feature distances within the group
of active molecules
 Tolerances on the distances matches account for the use of
discrete conformations
 and uncertainties in pharmacophore
 Used by DiscoTech
 When many pharmacophoric groups are present in the molecule it
may be very
 difficult to identify all possible combinations of the functional
groups
 Clique is defined as a 'maximal completely connected subgraph’

15. 3. Clique detection algorithm
Clique detection algorithms can be applied to a set of pre-calculated
conformations of the molecules.
Cliques are based upon the graph-theoretical approach to molecular
structure.