Drug discovery is being pursued through computer-aided design, synthesis, biological assaying, and crystallography. Lead identification is carried out by virtual screening (docking) or de novo design. Lead optimization is then driven by extensive results of Monte Carlo/free-energy perturbation simulations focusing on optimization of ring substituents, heterocycles, and linking groups. Successful applications are illustrated with recent results for HIV reverse transcriptase and both human and Plasmodium falciparum macrophage migration inhibitory factor (MIF); micromolar leads have been rapidly advanced to extraordinarily potent inhibitors. References:Jorgensen, W. L, Efficient Drug Lead Discovery and Optimization. Acc. Chem. Res. 2009  , 42, 724-733.Bollini, M.; Domaoal, R. A.; Thakur, V. V.; Gallardo-Macias, R.; Spasov, K. A.; Anderson, K. S.; Jorgensen, W. L. Computationally-Guided Optimization of a Docking Hit to Yield Catechol Diethers as Potent Anti-HIV Agents. J. Med. Chem. 2011  , 54, 8582-8591.

Efficient optimization of enzyme inhibitors via free energy calculations

245th National Meeting (2013)

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