Conformational analysis is used in pharmacophore mapping to identify the ideal conformation of a molecule that is biologically active. There are several methods to perform the conformational search, including systematic search, distance geometry, and clique detection algorithms. The systematic search method systematically varies torsion angles to generate conformations, while distance geometry randomly samples conformations. Clique detection algorithms search for common inter-feature distances within active molecules. The conformation search space can be large due to many possible torsion angle combinations, so these methods aim to efficiently explore the low-energy conformational space.

1. Conformational Search Used In Pharmacophore
Mapping

2. • 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
• Having several rotatable bonds results in a “combinatorial explosion”
• 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

3. 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)
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

4. Different methods
The conformation search can be quite large and can be approaches using following
methods
1. Systematic search method
2. Distance geometry method
3. Clique detection algorithm
1. Systematic search method
• Simplest
• Deterministic
• 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

5. Advantages:
• A deterministic approach, hence a
systematic exploration of
conformational space
• Can be used for small molecules or
systems with 10-15 bonds
Grid search Assumption: All bond lengths and angles remain fixed throughout the
calculation

6. E.g. : Deduce which features are required for activity Angiotensin-converting
enzyme (ACE), which is involved in regulating blood pressure

9. 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

10. 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

12. 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’
• 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

14.  Other methods:
 Model-building method
- Construct conformations of molecules by joining together three-dimensional
structures of molecular fragments
 Substructure search algorithm
– Substructure searching is finding a mapping for a query to a target molecule
– In other words, no bonds are broken and no new bonds are formed

15. Available Technologies
• CatConf, or ConFirm, from Accelrys that is part of the Discovery Studio
pharmacophore modeling protocols and tools provides two different search modes,
fast (systematic search) and best (distance geometry)
• The program systems CORINA and ROTATE available from Molecular Networks
• OMEGA from OpenEye Scientific Software is a fast systematic, knowledge-based
method
• MacroModel from Schrodinger is a very well-known and widely used force field-
based molecular modeling package and offers a variety of methods for conformation
generation
• CONFORT was developed by Prof. Pearlman, University of Texas, Austin and is
distributed by Tripos. CONFORT performs an exhaustive conformational analysis of
a molecule
• Some open source packages, such as Open Babel or RDKit, provide means to
generate sets of molecular conformations

16. Thank you……..