Molecular Dynamics Simulations and Structure-Based Rational Design Lead to Allosteric HCV NS5B Polymerase Thumb Pocket 2 Inhibitor with Picomolar Cellular Replicon Potency

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• 作者：Oliver Hucke ; Ren茅 Coulombe ; Pierre Bonneau ; M茅gan Bertrand-Laperle ; Christian Brochu ; James Gillard ; Marc-Andr茅 Joly ; Serge Landry ; Olivier Lepage ; Montse Llin脿s-Brunet ; Marc Pesant ; Martin Poirier ; Maude Poirier ; Ginette McKercher ; Martin Marquis ; George Kukolj ; Pierre L. Beaulieu ; Timothy A. Stammers
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：1932-1943
• 全文大小：715K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

The design and preliminary SAR of a new series of 1H-quinazolin-4-one (QAZ) allosteric HCV NS5B thumb pocket 2 (TP-2) inhibitors was recently reported. To support optimization efforts, a molecular dynamics (MD) based modeling workflow was implemented, providing information on QAZ binding interactions with NS5B. This approach predicted a small but critical ligand-binding induced movement of a protein backbone region which increases the pocket size and improves access to the backbone carbonyl groups of Val 494 and Pro 495. This localized backbone shift was consistent with key SAR results and was subsequently confirmed by X-ray crystallography. The MD protocol guided the design of inhibitors, exploiting novel H-bond interactions with the two backbone carbonyl groups, leading to the first thumb pocket 2 NS5B inhibitor with picomolar antiviral potency in genotype (gt) 1a and 1b replicons (EC₅₀ = 120 and 110 pM, respectively) and with EC₅₀ 鈮?80 nM against gt 2鈥?.