Optimization of Azoles as Anti-Human Immunodeficiency Virus Agents Guided by Free-Energy Calculations

@article{citeulike:2972957, abstract = {Abstract: Efficient optimization of an inactive 2-anilinyl-5-benzyloxadiazole core has been guided by free energy perturbation (FEP) calculations to provide potent non-nucleoside inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (NNRTIs). An FEP chlorine scan was performed to identify the most promising sites for substitution of aryl hydrogens. This yielded NNRTIs 8 and 10 with activities (EC50) of 820 and 310 nM for protection of human T-cells from infection by wild-type HIV-1. FEP calculations for additional substituent modifications and change of the core heterocycle readily led to oxazoles 28 and 29, which were confirmed as highly potent anti-HIV agents with activities in the 1020 nM range. The designed compounds were also monitored for possession of desirable pharmacological properties by use of additional computational tools. Overall, the trends predicted by the FEP calculations were well borne out by the assay results. FEP-guided lead optimization is confirmed as a valuable tool for molecular design including drug discovery; chlorine scans are particularly attractive since they are both straightforward to perform and highly informative.}, address = {Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, and Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066}, author = {Zeevaart, Jacob G. and Wang, Ligong and Thakur, Vinay V. and Leung, Cheryl S. and Tirado-Rives, Julian and Bailey, Christopher M. and Domaoal, Robert A. and Anderson, Karen S. and Jorgensen, William L. }, citeulike-article-id = {2972957}, doi = {http://dx.doi.org/10.1021/ja8019214}, journal = {J. Am. Chem. Soc.}, keywords = {application, free\_energy, relative}, month = {June}, posted-at = {2008-07-08 17:07:03}, priority = {2}, title = {Optimization of Azoles as Anti-Human Immunodeficiency Virus Agents Guided by Free-Energy Calculations}, url = {http://dx.doi.org/10.1021/ja8019214}, year = {2008} }

TY - JOUR ID - citeulike:2972957 L3 - citeulike-article-id:2972957 TI - Optimization of Azoles as Anti-Human Immunodeficiency Virus Agents Guided by Free-Energy Calculations JF - J. Am. Chem. Soc. AD - Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, and Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066 N2 - Abstract: Efficient optimization of an inactive 2-anilinyl-5-benzyloxadiazole core has been guided by free energy perturbation (FEP) calculations to provide potent non-nucleoside inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (NNRTIs). An FEP chlorine scan was performed to identify the most promising sites for substitution of aryl hydrogens. This yielded NNRTIs 8 and 10 with activities (EC50) of 820 and 310 nM for protection of human T-cells from infection by wild-type HIV-1. FEP calculations for additional substituent modifications and change of the core heterocycle readily led to oxazoles 28 and 29, which were confirmed as highly potent anti-HIV agents with activities in the 1020 nM range. The designed compounds were also monitored for possession of desirable pharmacological properties by use of additional computational tools. Overall, the trends predicted by the FEP calculations were well borne out by the assay results. FEP-guided lead optimization is confirmed as a valuable tool for molecular design including drug discovery; chlorine scans are particularly attractive since they are both straightforward to perform and highly informative. KW - application KW - free_energy KW - relative AU - Zeevaart, Jacob AU - Wang, Ligong AU - Thakur, Vinay AU - Leung, Cheryl AU - Tirado-Rives, Julian AU - Bailey, Christopher AU - Domaoal, Robert AU - Anderson, Karen AU - Jorgensen, William PY - 2008/06/28/ UR - http://dx.doi.org/10.1021/ja8019214 ER -