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Pharmacophore
- 1. PHARMACOPHORE Dr. Sachin Panwar JuniorResident Depatment of Pharmacology KGMU, Lucknow
- 2. THIS SLIDE ISONLY FOR EDUCATIONAL PURPOSE
- 3. • “An ensembleof steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response" -IUPAC
- 4. • Hydrogen-bond donorsand acceptors, positively and negatively charged groups, and hydrophobic regions are typical features
- 5. • A pharmacophoremodel explains how structurally diverse ligands can bind to a common receptor site. • Pharmacophore models can be used to identify potential leads through virtual screening of novel ligands that will bind to the same receptor.
- 6. HISTORY • Pharmacophores wereestablished by Lemont Kier. • He first mentions the concept in 1967 and uses the term in a publication in 1971
- 7. • Pharmacophore approacheshave become one of the major tools in drug discovery. • Various ligand-based and structure-based methods have been developed for improved pharmacophore modeling
- 8. • These methodshave been successfully and extensively applied in virtual screening, De novo design and lead optimization. • Despite these successes, pharmacophore approaches have not reached their expected full capacity
- 9. LIGAND BASED DESIGN Pharmcophore •Molecular framework that carries ( phoros) for drug’s, ( pharmacon) biological activity. • More important technique
- 10. QSAR( Quantitative structure& activity relationship) • Many actives & inactives - known compound of receptor • It is assumed that molecules having similar structure will have similar chemical properties.
- 11. QSAR • The informationprovided by a compound, or set of compounds known to bind to the desired target • This inf. is used to identify new compounds from the external databases of chemical compounds using machine learning methods
- 12. ZINC15 ( CHEMICALLIBRARIES) • A database of commercially-available compounds for virtual screening. • ZINC contains over 35 million purchasable compounds in ready-to- dock, 3D formats.
- 13. WHAT IS PHARMACOPHORE? •Common 3D arrangement of functionality that can be presented by all active molecules to interact with target receptor
- 14. Structure and function: •Molecular flexibility and shape are important • Conformational generation is necessary • Bits of the molecule which interact strongly and specifically with the binding site • Hydrogen bond groups, hydrophobes etc. presented by all active molecules.
- 15. Concept based oncomplimentary intreactions Source:google images
- 16. MODEL DEVELOPMENT • Theprocess for developing a pharmacophore model generally involves the following steps: 1) Select a training set of ligands – • Choose a structurally diverse set of molecules that will be used for developing the pharmacophore model.
- 17. 2).Conformational analysis – •Generate a set of low energy conformations • They are likely to contain the bioactive conformation for each of the selected molecules.
- 18. 3).Molecular superimposition – •Fit all combinations of the low-energy conformations of the molecules. • Similar functional groups common to all molecules in the set might be fitted (e.g., phenyl rings or carboxylic acid groups). • The set of conformation that results in the best fit is presumed to be the active conformation.
- 19. 4).Abstraction – • Transformthe superimposed molecules into an abstract representation. • e.g. superimposed phenyl rings might be referred to more conceptually as an 'aromatic ring' pharmacophore element. • Hydroxy groups could be designated as a 'hydrogen- bond donor/acceptor' pharmacophore element.
- 20. 5).Validation – • Apharmacophore model is a hypothesis accounting for the observed biological activities of a set of molecules that bind to a common biological target. • The model is only valid in so far as it is able to account for differences in biological activity of a range of molecules.
- 21. • As thebiological activities of new molecules become available, the pharmacophore model can be updated to further refine it.
- 22. AUTOMATED PHARMACOPHORE MODELLINGMETHODS • HypoGen dataset • Structurally diverse PREDICTIVE MODEL • Activity data required HypoGen • HipHop dataset • 2-32 molecules A TRUE • Activity data not required PHARMACOPHORE • Input molecules must be active Model
- 23. APPLICATIONS • Pharmacophores areused to define the essential features of one or more molecules with the same biological activity. • A database of diverse chemical compounds can then be searched for more molecules which share the same features arranged in the same relative orientation.
- 24. • Pharmacophores arealso used as the starting point for developing new drug models. Aid in drug discovery
- 25. SOSA: NEW LEADSFROM OLD DRUGS • Selective Optimization of Side Activities • Start screening with a limited set of carefully chosen, structurally diverse, drug molecules. • Already bioavailability and toxicity studies have been performed and as they have proven usefulness in human therapy.
- 26. Optimize hits • Inorder to increase the affinity for the new target and decrease the affinity for the other targets.
- 27. DIFFERENT TYPES OFPHARMACOPHORE SEARCHING SOFTWARES Software Description Pharmer It is efficient pharmacophore tool for virtual screening and it takes only one pdb file at a time. Pharmapper It contains a database repository of about 7000 targets based pharmacophore models. Based on triangle hashing based method. PharmaGist PharmaGist used for searching pharmacophore from a set of ligand molecules. It requires the set of ligands known to interact with a particular target without any prior knowledge of target structure. Boomer It is freely available pharmacokinetic drug monitering. ZincPharma It is used for screening of zinc database. Pkfit PKfit is a tool for pharmacokinetic modeling. JPKD It is a therapeutic drug monitoring tool.
- 28. WORKING OF PHARMACOPHORE PHAMACOPHOREMODEL: • Explains how structurally diverse ligands can bind to a common receptor site
- 29. WORKING OF PHARMACOPHORE TypicalPharmcophore factors: • Hydrophobic centroids -CH3, -C2H5 • Aromatic Rings • Hydrogen bond acceptors • Hydrogen bond donors -OH, -NH • Cations & Anions
- 30. WORKING OF PHARMACOPHORE •1st identify Pharmacophore • Then identify diverse chemical compounds which share same features using database
- 31. EXAMPLE ( WORKINGOF PHARMACOPHORE) • Selective COX-2 inhibitors • Valdecoxib, Rofecoxib, Celecoxib Source: google images
- 32. PHARMAGIST • Its freelyavailable on web for Pharmacophore detection • It is ligand based • Doesn’t require structure of target receptors • GO to web address: http://bioinfo3d.cs.tau.ac.il/PharmaGist/php.php
- 33.
- 34. • mol2 format •Consists of structures of celecoxib, valdecoxib, rofecoxib • Upload the file • Results comes on email.
- 36. • We seethe Highest scores.
- 37. • NOW, • Wego to Pymol • Construct Pharmacophore design using: - No. of ATOMS - HYDROGEN acceptors/donors - No. of Hydrophobic bonds etc.
- 38.
- 39. COMPARING WITH COX-2RECEPTOR Source: google images
- 40. • Go toZINC 15, ZINC PHARMER Like databases • Upload PHARMACOPHORE in mol2 • Retrieve molecules which have same structure
- 41.
- 42. RETRIEVED MOLECULES FROMDATABASES Source: ZINC15
- 43. • Select moleculeswith lowest Energy • Test best molecules for activity
- 44. FINGERPRINTING STIMULATION • Partof chemiinformatics • Stimulation coefficents( TANIMOTO/ JACCARD) • HIGH for similar structures
- 45. • Onlinecalculator forTANIMOTO- ChemMine TOOL.
- 46. SUMMARY • A pharmacophoremodel explains how structurally diverse ligands can bind to a common receptor site. • MOST IMPORTANT EVOVING TECHNIQUE FOR DRUG DISCOVERY. • Different types of pharmacophore searching softwares Pharmer, PharmaGist, ZincPharma etc
- 47.