Lecture 10 pharmacophore modeling and sar paradox
- 1. Lecture 10- Pharmacophore Modeling and SAR paradox BTT- 516– Drug Designing and Development
- 2. A pharmacophore is a specific 3D arrangement of functional groups within a molecular framework that are necessary to bind to a macromolecule and/or an enzyme active site The identification of pharmacophore is important step in understanding the interactions between a receptor and a ligand Pharmacophore
- 3. Pharmacophore approaches are successful subfields of computer-aided drug design (CADD) which have become one of the major tools in hit identification, lead optimization, and rational design of novel drugs. 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. Every type of atom or group in a compound can be reduced to a pharmacophore feature (or pharmacophore fingerprints). These molecular patterns would be labeled by several chemical properties, such as hydrogen bond donors or acceptors, aromatic, cationic, etc, which can be used to analyze the similarity among a library of small molecules and identify the key contributing features to the biological function. Pharmacophore Modeling
- 5. 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. 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.
- 6. 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. Purpose of pharmacophore modeling Why pharmacophore is important? Pharmacophore is the essential to understand the interaction between the receptor and ligand. It is important feature to design new drug for treatment of the intended disease. Pharmacophore defined as the essential geometric arrangement of atoms or functional groups necessary to produce a given biological response.
- 8. Qing X, Lee XY, De Raeymaecker J, Tame JR, Zhang KY, De Maeyer M, Voet A. Pharmacophore modeling: advances, limitations, and current utility in drug discovery. Journal of Receptor, Ligand and Channel Research. 2014;7:81-92.
- 9. SAR paradox and concept of force field The structure–activity relationship (SAR) is the relationship between the chemical structure of a molecule and its biological activity. Structure-Activity Relationship (SAR) is an approach designed to find relationships between chemical structure (or structural-related properties) and biological activity (or target property) of studied compounds.
- 10. The basic assumption for all molecule based hypotheses is that similar molecules have similar activities. This principle is also called Structure-Activity Relationship (SAR). The underlying problem is therefore how to define a small difference on a molecular level, since each kind of activities Examples: Reaction ability, Biotransformation ability, Solubility, target activity, and so on, might depend on another difference. A good example was given in the bioisosterism review of Patanie/LaVoie. In general, one is more interested in finding strong trends. Created hypotheses usually rely on a finite number of chemical data. Thus, the induction principle should be respected to avoid overfitted hypotheses and deriving overfitted and useless interpretations on structural/molecular data. The SAR paradox refers to the fact that it is not the case that all similar molecules have similar activities.
- 15. Thank you Er. Rajan Rolta Faculty of Applied Sciences and Biotechnology Shoolini University, Village Bhajol, Solan (H.P) +91-7018792621 (Mob No.) rajanrolta@shooliniuniversity.com