Targeting Dynamic Pockets of HIV-1 Protease by Structure-Based Computational Screening for Allosteric Inhibitors

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• 作者：Jens Kunze ; Nickolay Todoroff ; Petra Schneider ; Tiago Rodrigues ; Tim Geppert ; Felix Reisen ; Herman Schreuder ; Joachim Saas ; Gerhard Hessler ; Karl-Heinz Baringhaus ; Gisbert Schneider
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2014
• 出版时间：March 24, 2014
• 年：2014
• 卷：54
• 期：3
• 页码：987-991
• 全文大小：329K
• 年卷期：v.54,no.3(March 24, 2014)
• ISSN：1549-960X

文摘

We present the discovery of low molecular weight inhibitors of human immunodeficiency virus 1 (HIV-1) protease subtype B that were identified by structure-based virtual screening as ligands of an allosteric surface cavity. For pocket identification and prioritization, we performed a molecular dynamics simulation and observed several flexible, partially transient surface cavities. For one of these presumable ligand-binding pockets that are located in the so-called 鈥渉inge region鈥?of the identical protease chains, we computed a receptor-derived pharmacophore model, with which we retrieved fragment-like inhibitors from a screening compound pool. The most potent hit inhibited protease activity in vitro in a noncompetitive mode of action. Although attempts failed to crystallize this ligand bound to the enzyme, the study provides proof-of-concept for identifying innovative tool compounds for chemical biology by addressing flexible protein models with receptor pocket-derived pharmacophore screening.