Knowledge-Based Scoring Functions in Drug Design. 1. Developing a Target-Specific Method for Kinase−Ligand Interactions

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• 作者：Mengzhu Xue ; Mingyue Zheng ; Bing Xiong ; Yanlian Li ; Hualiang Jiang ; Jingkang Shen
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2010
• 出版时间：August 23, 2010
• 年：2010
• 卷：50
• 期：8
• 页码：1378-1386
• 全文大小：356K
• 年卷期：v.50,no.8(August 23, 2010)
• ISSN：1549-960X

文摘

Protein kinases are attractive targets for therapeutic interventions in many diseases. Due to their importance in drug discovery, a kinase family-specific potential of mean force (PMF) scoring function, kinase-PMF, was developed to assess the binding of ATP-competitive kinase inhibitors. It is hypothesized that target-specific PMF scoring functions may achieve increased performance in scoring along with the growth of the PDB database. The kinase-PMF inherits the functions and atom types in PMF04 and uses a kinase data set of 872 complexes to derive the potentials. The performance of kinase-PMF was evaluated with an external test set containing 128 kinase crystal structures. We compared it with eight scoring functions commonly used in computer-aided drug design, either in terms of the retrieval rate of retrieving “right” conformations or a virtual screening study. The evaluation results clearly demonstrate that a target-specific scoring function is a promising way to improve prediction power in structure-based drug design compared with other general scoring functions. To provide this rescoring service for researchers, a publicly accessible Web site was established at http://202.127.30.184:8080/scoring/index.jsp.