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Targeting flexibility: a structure-based computational study revealing allosteric HIV-1 protease inhibitors

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We present the discovery of innovative low molecular weight inhibitors against human immunodeficiency virus 1 (HIV-1) protease. Structure-based virtual screening focused on potential allosteric surface cavities revealed these compounds [1]. To identify and prioritize such cavities we performed a molecular dynamics simulation were we concentrated on flexible and transient potential binding sites. For several time-points of the simulation we computed receptor-derived pharmacophore models in the so-called hinge region ('Exo site') and screened a large screening compound library [2]. The most potent hit shows inhibition in a non-competitive mode of action.

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    Weisel M, Proschak E, Schneider G: Chem Cent J. 2007, 1: 7-10.1186/1752-153X-1-7.

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    Weisel M, Geppert T, Schneider P, Hoy B, Wessler S, Schneider G: PLoS One. 2011, 6: 3-

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Correspondence to Jens Kunze.

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Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Kunze, J., Todoroff, N., Rodrigues, T. et al. Targeting flexibility: a structure-based computational study revealing allosteric HIV-1 protease inhibitors. J Cheminform 6, P48 (2014) doi:10.1186/1758-2946-6-S1-P48

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Keywords

  • Virtual Screening
  • Hinge Region
  • Pharmacophore Model
  • Surface Cavity
  • Compound Library