PI-710: Strategies in Lead Optimization |
(2 credits) |
1. | Introduction: Overview of strategies; Lead optimization; Drug discovery cycle; Success story of captopril. |
2. | De novo ligand design: Overview; Active site analysis method; Whole molecule method; Connection methods; Genetic algorithm for ligand building; Limitations; Software. |
3. | Structure based drug design: Introduction; Bioactive conformation; Ligand anchoring; Desolvation effect; Entropic effect; Role of water; Analog design; Data base searching; De novo design; Success stories. |
4. | Iterative Protein crystallographic analysis: Introduction; Experimental approaches; Role of crystallography in drug design; Conformation and biological ac. Advantages and limitations of crystallography; Applications; Case studies. |
5. | Docking and Scoring: Molecular recognition. Methods, algorithms, conformational ensemble, molecular determinants for binding, scoring functions, solvation effect. In silico tools, flexible docking, Applications, case studies. |
6. | Small molecular crystallography: Introduction, direct and indirect design, CSD, bioactive conformation, polar and non-polar molecules, crystal packing and ligand protein interaction. Data base mining, CHO hydrogen bonding, and applications. |
7. | Peptidomimetics: Introduction, types of peptidomimetics, conformational restriction, template mimetics, peptide bond isosteres, transition state analogs, rational drug design. Case studies. |
8. | ADMET and Duggability: Property based drug design, absorption, distribution, metabolism, excretion and physicochemical properties. Descriptors, bioisosterism, prodrug and soft drug approaches. |
9. | Metabolism by Cytochromes: Introductions, significance of cytochrome P450s, substrates and inhibitors, predicting cytochrome P450 metabolism; Ligand based and structure based models for cytochrome P450. Case studies. |
10. | Human ether-a-go-go-related gene (hERG): Introduction, cardiac arrhythmias, SAR around hERG, in silico approaches. Examples. |
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