Pharmacophore modeling
- 2. Ligand in catalytic pocket Protein(Cysteine Protease) Protein with Ligand
- 3. Pharmacophore identification • Pharmer • Pharmapper • Pharmagist • Boomer • ZincPharmer
- 4. Pharmacophore • The original concept of the pharmacophore was developed by Paul Ehrlich during the late 1800s. • The word pharmacophore was coined much later, by Schueler in his 1960 book Chemobiodynamics and Drug Design, and was defined as “a molecular framework that carries (phoros) the essential features responsible for a drug’s (pharmacon) biological activity.” • The definition of a pharmacophore was therefore no longer concerned with “chemical groups” but “patterns of abstract features.
- 5. Pharmacophore • International Union of Pure and Applied Chemistry “A pharmacophore is the ensemble of 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” • Significance • Pharmacophores can be used to represent and identify molecules on a 2D or 3D level by schematically. • The most common application of pharmacophores is virtual screening, and different strategies are possible depending on the prior knowledge • The pharmacophore concept is also useful for ADME-tox modeling, side effect, and off-target prediction as well as target identification.
- 6. Pharmacophore Features • Hydrogen Bond Donor • Hydrogen Bond Acceptor • Aromatic • Hydrophobicity • Hydrophilic
- 7. Pharmacophore modeling • Pharmacophore modeling is most often applied to virtual screening in order to identify molecules triggering the desired biological effect. • For this purpose, researchers create a pharmacophore model (query) that most likely encodes the correct 3D organization of the required interaction pattern. Depending on how much is known about the particular protein target, different options are available to construct such a query
- 9. Pharmacophore modeling • A pharmacophore model is the ensemble of common steric and electronic features that are necessary to ensure the optimal molecular interactions with a specific biological target and to trigger (or block) its biological response. It can be used to represent and characterize molecules on schematic 2D or 3D level by identifying the essential properties of molecular recognition.
- 10. Pharmacophore modeling Ligand-based pharmacophore modeling: In the absence of the macromolecular target structure, ligand-based pharmacophore modeling is an essential strategy for drug discovery. In this method, the common chemical characteristics from 3D structures of multiple known ligands are extracted through ligand alignment, which would represent the essential interactions between ligand and potential macromolecular target.
- 11. Pharmacophore modeling Structure-based pharmacophore modeling: The structure-based pharmacophore modeling generates chemical features of the active site and the sterical relationships from 3D structure of macromolecular target or macromolecule-ligand complex. It probes the possible interaction sites between the macromolecular target and the ligands.