Pharmacophore mapping and virtual screening

CONCEPT OF PHARMACOPHORE
PHARMACOPHORE MAPPING
IDENTIFICATION OF PHARMACOPHORE FEATURE
CONFORMATIONAL SEARCH
INSILICO DRUG DESIGN
VIRTUAL SCREENING
PHARMACOPHORE BASED SCREENING
First introduced by Paul Heritich in 1990
A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule.
It is the key features responsible for an activity (eg. Substrates, inhibitors)
A pharmacophore is a representation of generalized molecular features including;
3D (hydrophobic group, chaeged /ionisable group, hydrogen bond donar/ acceptor)
2D (substructure)
1D (physical & biological)
 Pharmacophore Mapping is the definition and placement of pharmacophoric features and the alignment techniques used to overlay 3D.
Two somewhat distinct usages:
That substructure of a molecule that is responsible for its pharmacological activity (c.f. chromophore)
A set of geometrical constraints between specific functional groups that enable the molecule to have biological activity
 The process of deriving pharmacophore is known as pharmacophore mapping.

1. PHARMACOPHORE MAPPING AND VIRTUAL SCREENING By;- Sanchit Dhankhar Pharmacology Department

2. CONCEPT OF PHARMACOPHORE PHARMACOPHORE MAPPING IDENTIF I C A TION OF P HARMACOPHORE F E A TU R E CONFORMATIONAL SEARCH INSILICO DRUG DESIGN VIRTUAL SCREENING PHARMACOPHORE BASED SCREENING 2

3. First introduced by Paul Heritich in 1990 A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule. It is the key features responsible for an activity (eg. Substrates, inhibitors) A pharmacophore is a representation of generalized molecular features including; 3D (hydrophobic group, chaeged /ionisable group, hydrogen bond donar/ acceptor) 2D (substructure) 1D (physical & biological) H Aroma t ic HBA R HBD 3

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5.  Pharmacophore Mapping is the definition and placement of pharmacophoric features and the alignment techniques used to overlay 3D. Two somewhat distinct usages: That substructure of a molecule that is responsible for its pharmacological activity (c.f. chromophore) A set of geometrical constraints between specific functional groups that enable the molecule to have biological activity  The process of deriving pharmacophore is known as pharmacophore mapping. 5

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8. Identifying common binding element that are responsible for the biological activity; Generating potential conformations that active compound may adopt; and Determining the 3D relationship between pharmacophore element in each conformation generated. 8

9. X-ray Crystallography Structure Comparison of active compound Automatic identification of pharmacophore 9

10. 4)PHARMACOPHORE MAPPING SOFTWARE Discovery studio : Window ® and Linux® based protein modeling software. Produced by Accelrys software company, easy to use interface. Examples of the programs that perform pharmacophore based searches are 3D search UNITY, MACCS-3D and ROCS. ROCS is using as shape based super position for identifying compound that have similar shaped. 10

11. 5) CONFORMATIONAL SEARCH X -ray Crystallography Comparison of rigid & non rigid ligands 11

12. In Silico is an expression used to mean “performed on computer or via computer simulation.” In Silico drug designing is defined as the identification of the drug target molecule by employing bioinformatics tools . 12

13. LIGAND BASED DRUG DESIGNING STRUCTURE BASED DRUG DESIGNING IN SILICO DRUG DESIGNING 13

14. 1.Structure-based 14 (know receptor, don’t known ligands) Relies on knowledge of the three dimensional structure of the biological target obtained through methods such as x-ray crystallography NMR spectroscopy. homology modeling Using the structure of the biological target, drugs that are predicted to bind with to the target may be designed using interactive graphics the intuition of a medicinal chemist. automated computational procedures

15. 2. Ligand-based ( don’t know receptor, known ligands Protein/ligand) Relies on knowledge of other molecules that bind to the biological target of interest. Used to derive a pharmacophore 15

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18. Computational technique. Producing large libraries of compound that docked in to the binding site using computer programme. The goal is finding interesting new scaffolds rather than many hits. Low hits rate are clearly very preferable. 18

19. Usually pharmacophore based search are done in two steps. First the software checks whether the compound has the atom types or functional groups required by the pharmacophore, than its checks whether the spatial arrangement of this element matches the query. Flexible 3D searches identified a higher number of hits than rigid searches do. However flexible searches are more time consuming than rigid ones. There are two main approaches for including conformational flexibility in to the search one is top generate a user defined number of representative conformation for each molecules when the database is to created, the other is to generate conformation during the search. 19

20. Pharmacophore model provide powerful filter tools for virtual screening even in case where the protein structure is not available, pharmacophore filter are much faster than docking approaches, and there for greatly reduce the number of compound subjected to the more expensive docking application. Another interesting aspect of pharmacophore in virtual screening is 3D- pharmacophore diversity 20

21. Patrik G. L., an introduction to medicinal chemistry, 3 rd edition, page no. 340-345 www.en.wikipedia.org ht t ps: / / w w w .sl i deshare.n e t> G a m i t Kin ja l/ph a r m acopho r e - mapping-05 ht t ps: / / w w w .sl i deshare.n e t / m obi l e/ c hinexc e e/pha r m acopho r e - mapping-in-drug- development http://m.authorstream.com/presentation/aSGuest126841- 1335009-pharmacophore-mapping/ https:/ /w w w.slideshare.net/mobile/Deveshshukla 10/in-silico- drug-designing 21

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