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.