Incorporating Dynamics in E. coli Dihydrofolate Reductase Enhances Structure-Based Drug Discovery

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• 作者：Michael G. Lerner ; Anna L. Bowman ; Heather A. Carlson
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2007
• 出版时间：November 2007
• 年：2007
• 卷：47
• 期：6
• 页码：2358 - 2365
• 全文大小：600K
• 年卷期：v.47,no.6(November 2007)
• ISSN：1549-960X

文摘

Escherichia coli dihydrofolate reductase (DHFR) is a long-standing target for enzyme studies. The influenceof protein motion on its catalytic cycle is significant, and the conformation of the M20 loop is of particularinterest. We present receptor-based pharmacophore models-an equivalent of solvent-mapping of bindinghotspots-based on ensembles of protein conformations from molecular dynamics simulations of DHFR·NADPH in both the closed and open conformation of the M20 loop. The optimal models identify DHFRinhibitors over druglike noninhibitors; furthermore, high-affinity inhibitors of E. coli DHFR are preferentiallyidentified over general DHFR inhibitors. As expected, models resulting from simulations with DHFR in theproductive conformation with a closed M20 loop have better performance than those from the open-loopsimulations. Model performance improves with increased dynamic sampling, indicating that including agreater degree of protein flexibility can enhance the quest for potent inhibitors. This was compared to thelimited conformational sampling seen in crystal structures, which were suboptimal for this application.