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Computer-Aided Approaches for Targeting HIVgp41
Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794, USA
Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794, USA
Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, USA
* Author to whom correspondence should be addressed.
Received: 17 July 2012; in revised form: 9 August 2012 / Accepted: 12 August 2012 / Published: 20 August 2012
Abstract: Virus-cell fusion is the primary means by which the human immunodeficiency virus-1 (HIV) delivers its genetic material into the human T-cell host. Fusion is mediated in large part by the viral glycoprotein 41 (gp41) which advances through four distinct conformational states: (i) native, (ii) pre-hairpin intermediate, (iii) fusion active (fusogenic), and (iv) post-fusion. The pre-hairpin intermediate is a particularly attractive step for therapeutic intervention given that gp41 N-terminal heptad repeat (NHR) and C‑terminal heptad repeat (CHR) domains are transiently exposed prior to the formation of a six-helix bundle required for fusion. Most peptide-based inhibitors, including the FDA‑approved drug T20, target the intermediate and there are significant efforts to develop small molecule alternatives. Here, we review current approaches to studying interactions of inhibitors with gp41 with an emphasis on atomic-level computer modeling methods including molecular dynamics, free energy analysis, and docking. Atomistic modeling yields a unique level of structural and energetic detail, complementary to experimental approaches, which will be important for the design of improved next generation anti-HIV drugs.
Keywords: HIV; AIDS; gp41; T20; structural biology; structure-based drug design; computer-aided drug design; molecular dynamics; docking; DOCK
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MDPI and ACS Style
Allen, W.J.; Rizzo, R.C. Computer-Aided Approaches for Targeting HIVgp41. Biology 2012, 1, 311-338.
Allen WJ, Rizzo RC. Computer-Aided Approaches for Targeting HIVgp41. Biology. 2012; 1(2):311-338.
Allen, William J.; Rizzo, Robert C. 2012. "Computer-Aided Approaches for Targeting HIVgp41." Biology 1, no. 2: 311-338.