Impact of Mobility on Structure-Based Drug Design for the MMPs

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• 作者：Franklin J. Moy ; Pranab K. Chanda ; James Chen ; Scott Cosmi ; Wade Edris ; Jeremy I. Levin ; Thomas S. Rush ; James Wilhelm ; and Robert Powers
• 刊名：Journal of the American Chemical Society
• 出版年：2002
• 出版时间：October 30, 2002
• 年：2002
• 卷：124
• 期：43
• 页码：12658 - 12659
• 全文大小：114K
• 年卷期：v.124,no.43(October 30, 2002)
• ISSN：1520-5126

文摘

Structure-based approaches for drug design generally do not incorporate solvent effects and dynamic information to predict inhibitor-binding affinity because of practical limitations. The matrix metalloproteinases (MMPs) have previously been demonstrated to exhibit significant mobility in their active sites. This dynamic characteristic significantly complicates the drug design process based on static structures, which was clearly observed for a class of hydroxamic acids containing a butynyl moiety. Compound 1 was expected to be selective against MMP-1 based on predicted steric clashes between the butynyl P1' group and the S1' pocket, but the observation of complex inhibitor dynamics in the NMR structure of MMP-1:1 provides an explanation for the low nanomolar binding to MMP-1.