1. Computer-Assisted Drug Design (1) i)Random Screening ii)Lead Development and Optimization using Multivariate Statistical Analyses. iii)Lead Generation – Structure Based Drug Design using Computer Graphics and Computer Chemistry.

2. Computer-Assisted Drug Design (2) Structure Based Drug Design i)Computer Graphics ii)Docking Study using Molecular Mechanics iii)Lead Generation i)Generate Novel Compounds that Fit to the Pharmacophore Features ii)Optimize their Chemical Structures using Molecular Mechanics and Molecular Dynamics.

3. Procedure of Structure Based Drug Design (Lead Generation) i)Determine 3D structure of a target protein using X-ray crystallography and NMR (Nuclear Magnetic Resonance) ii)Generate chemical structure that fits to the pharmacophore of the protein Using Computer Graphics, etc. iii)Compute the interaction energy between the compound and the protein. iv)Optimize the chemical structure in order to maximize the interaction energy

5. Experimental Methods for Determining 3D Structures of Proteins 1) X-ray crystallography ・ more accurate than NMR ・ crystal has to be grown to a sufficient size and volume 2) NMR ・ information about flexibility ・ no need for crystals ・ easy to change conditions (pH, temperature, etc.) ・ size limit

6. A Computational Method for Determining 3D Structures of Proteins Homology Modeling using Sequence Homology 1.Identify homologous proteins and determine the extent of their sequence similarity with one another and the unknown 2.Align the sequences 3. Identify structurally conserved and structurally variable regions 4. Generate coordinates for core (structurally conserved) residues of the unknown structure from those of the known structure(s) 5.Generate conformations for the loops (structurally variable) in the unknown structure 6.Build the side-chain conformations 7.Refine and evaluate the unknown structure. http://cl.sdsc.edu/hm.html

7. Determination of Molecular Structure Using Moolecular Mechanics E total = E stretch + E bend + E torsion + E vdW + E dipole E stretch E bend E torsion E vdW minimize

8. Molecular Dynamics Calculation 1)Determine the initial positions and the initial velocities of the atoms 2)Compute Forces using the equation, 3)According to the equation of motion, F=ma, Compute the next position of the atoms

9. Molecular Dynamics Calculation