For the last ten years we have pursued the prospective use of free energy perturbation calculations for lead optimization. The successes and problems will be reviewed. Some key issues are confidence in the structure of protein-ligand complexes, force fields, atomic charge models, configurational sampling, Monte Carlo vs. molecular dynamics, and accuracy of assays. The status of computing absolute free energies of binding will also be addressed. The illustrated applications are primarily for the design of inhibitors targeting HIV-1 reverse transcriptase and macrophage migration inhibitory factor.

Current issues with computer-aided lead optimization

251st National Meeting (2016)

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