MC-610: Drug Design		(2 credits)
1.	Wave function of drug molecules. Hamiltonian of Drugs. Absolute and relative energies of drug conformers. The importance of postulate 4 over postulate 3 in obtaining energy drugs. Energy minimization, comparison between global minimum conformation and bioactive conformation.
2.	Manual and automated conformational search methods, their advantages and disadvantages. Implicit and explicit solvent effects on the structures of drugs. Conformational interconversion, transition-state determination and their role in designing rigid analogs. Molecular graphics. Computer methodologies behind molecular modeling including artificial intelligence methods.
3.	Semi-empirical methods, molecular mechanical methods. Biguanides, nitreons in drugs, rapid racemization in glitazones, metabolism and toxicity of troglitazone, conversion of proguanil to cycloguanil.
4.	QSAR: Steric and electronic effects: Hammett equation, lipophilicity effects. Hansch equation. Experimental and theoretical approaches for the determination of physico-chemical parameters, descriptors from Graph theory. Regression analysis, extrapolation versus interpolation, linearity versus nonlinearity. Descriptor calculation. The importance of biological data in the correct form; 2D QSAR; 3D-QSAR examples of CoMFA and CoMSIA. 4,5 and 6D QSAR methods.
5.	Molecular Docking: Rigid docking, flexible docking, manual docking, induced fit docking. Algorithms for molecular docking. Advantages and disadvantages of Glid, GOLD, Autodock and Dock software, with successful examples.
6.	Pharmacophore Perception: Unity in diversity; common minimum feature identification. Pharmacophore mapping techniques, methods of conformational search used in pharmacophore mapping. Comparison between the popular pharmacophore methods like Catalyst/HipHop, DiscoTech, GASP with practical examples.
7.	Molecular Dynamics: Trajectories – structural, energy, interaction. Dynamics of drugs, dynamics of biomolecules, dynamics of drug-receptor complexes. Molecular dynamics in estimation of free energy from dynamical methods. Entropy and van der Waals vs. electrostatic component. Residuewise interaction energy estimation using MD simulations. Human vs. PfDHFR interaction energy difference with P218.
8.	De novo Design: Active sites, allosteric sites, subpockets. Receptor/enzyme cavity size prediction. Predicting the functional components of cavities, designing drugs fitting into cavity. Trypanothione inhibitor Design using De novo design strategies.
9.	Virtual Screening: Protocol development in virtual screening. Qualitative versus quantitative approaches- advantages and disadvantages. Random screening, Non-random screening, drug metabolism studies, clinical observations, rational approaches to lead discovery.
10.	Case studies: Anti-malarial agent design using CADD methods (PfDHFR), Anti-diabetic agent design (GSK3), anti-cancer agent design (TopoisomeraseII), Anti-leishmanial agent design (TR inhibitors).