Crystal structures of HIV-1 reverse transcriptase complexes with thiocarbamate non-nucleoside inhibitors

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• 作者：Andrea Spallarossa ; Sara Cesarini ; Angelo Ranise ; Marco Ponassi ; Torsten Unge ; Martino Bolognesi
• 关键词：HIV-1 ; Reverse transcriptase ; X-ray crystallography ; Non-nucleoside reverse transcriptase inhibitors ; Thiocarbamates
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2008
• 出版时间：25 January 2008
• 年：2008
• 卷：365
• 期：4
• 页码：764-770
• 全文大小：969 K

文摘

O-Phthalimidoethyl-N-arylthiocarbamates (TCs) have been recently identified as a new class of potent HIV-1 reverse transcriptase (RT) non-nucleoside inhibitors (NNRTIs), by means of computer-aided drug design techniques [Ranise A. Spallarossa, S. Cesarini, F. Bondavalli, S. Schenone, O. Bruno, G. Menozzi, P. Fossa, L. Mosti, M. La Colla, et al., Structure-based design, parallel synthesis, structure–activity relationship, and molecular modeling studies of thiocarbamates, new potent non-nucleoside HIV-1 reverse transcriptase inhibitor isosteres of phenethylthiazolylthiourea derivatives, J. Med. Chem. 48 (2005) 3858–3873]. To elucidate the atomic details of RT/TC interaction and validate an earlier TC docking model, the structures of three RT/TC complexes were determined at 2.8–3.0 Å resolution by X-ray crystallography. The conformations adopted by the enzyme-bound TCs were analyzed and compared with those of bioisosterically related NNRTIs.