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Abstract
Rational Design and Synthesis of Anti-HIV Drugs
Jorgensen W.1, Ruiz-Caro J.1, Tirado-Rives J.1
1Yale University, New Haven, CT, United States of America
Introduction: Anti-HIV drug development is being pursued through computer-aided design, synthesis, and assaying [Science,
303, 1813-1818 (2004)].The current goal is the development of easily synthesized non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) that remain active against mutant forms of the virus.
Methods: BOMB, a program that grows inhibitors in binding sites (www.cemcomco.com), has been used to construct thousands of potential NNRTIs, which have been scored for potential activity and filtered for good pharmacological properties with QikProp (www.schrodinger.com). Further lead refinement has been carried out using Monte Carlo simulations with free-energy perturbation theory. The most promising compounds have been synthesized and their anti-HIV activities have been evaluated in MTT cell proliferation assays.
Results: The computational methodology yields accurate predictions for the structures of protein-inhibitor complexes and the effects of protein mutations on activity; correct predictions, subsequently confirmed by X-ray crystallography, were made for the structures of the complexes of HIV-1 reverse transcriptase with evafirenz and TMC125 [J Am Chem Soc
122, 12898-12900 (2000);
125, 6016-6017 (2003)]. The results have also led to resolution of differences in crystal structures [J Med Chem
46, 2389-2392 (2004)] and to design principles for development of inhibitors that inactivate the wild-type enzyme as well as mutant forms [Bioorg Med Chem Lett
11, 2799-2802 (2001)]. Application of the approach has led to a promising series of phenylthiazoylamines; synthesis and lead-optimization including assay work with infected MT-2 cells have been extensively pursued and have led to new, potent NNRTIs with notably improved properties, especially aqueous solubility.
Conclusions: Computational methodology coupled with synthesis and cell-based assaying has been applied successfully to the design of next generation NNRTIs.
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