Nonfitting protein-ligand interaction scoring function based on first-principles theoretical chemistry methods: Development and application on kinase inhibitors

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	Nonfitting protein-ligand interaction scoring function based on first-principles theoretical chemistry methods: Development and application on kinase inhibitors
	Rao, Li ; Zhang, Igor Ying ; Guo, Wenping ; Feng, Li ; Meggers, Eric ; Xu, Xin ; Xu X(徐昕) ; ERIC MEGGERS
刊名	http://dx.doi.org/10.1002/jcc.23303
	2013
关键词	QUANTUM MECHANICS/MOLECULAR MECHANICS MOLECULAR-ORBITAL METHODS EXTENDED ONIOM METHOD 2 CDK2 INHIBITORS THERMOCHEMICAL KINETICS DENSITY FUNCTIONALS TRANSITION-ELEMENTS GUANINE DERIVATIVES ORGANIC-MOLECULES BINDING
英文摘要	National Natural Science Foundation of China [91027044, 21133004, 20923004]; Ministry of Science and Technology of China [2013CB834606, 2011CB808505]; Targeted therapy is currently a hot topic in the fields of cancer research and drug design. An important requirement for this approach is the development of potent and selective inhibitors for the identified target protein. However, current ways to estimate inhibitor efficacy rely on empirical protein-ligand interaction scoring functions which, suffering from their heavy parameterizations, often lead to a low accuracy. In this work, we develop a nonfitting scoring function, which consists of three terms: (1) gas-phase protein-ligand binding enthalpy obtained by the eXtended ONIOM hybrid method based on an integration of density functional theory (DFT) methods (XYG3 and B97X-D) and the semiempirical PM6 method, (2) solvation free energy based on DFT-SMD solvation model, and (3) entropy effect estimated by using DFT frequency analysis. The new scoring function is tested on a cyclin-dependent kinase 2 (CDK2) inhibitor database including 76 CDK2 protein inhibitors and a p21-activated kinase 1 (PAK1) inhibitor database including 20 organometallic PAK1 protein inhibitors. From the results, good correlations are found between the calculated scores and the experimental inhibitor efficacies with the square of correlation coefficient R2 of 0.76-0.88. This suggests a good predictive power of this scoring function. To the best of our knowledge, this is the first high level theory-based nonfitting scoring function with such a good level of performance. This scoring function is recommended to be used in the final screening of lead structure derivatives. (c) 2013 Wiley Periodicals, Inc.
语种	英语
出版者	WILEY-BLACKWELL
内容类型	期刊论文
源URL	[http://dspace.xmu.edu.cn/handle/2288/88972]
专题	化学化工－已发表论文
推荐引用方式 GB/T 7714	Rao, Li,Zhang, Igor Ying,Guo, Wenping,et al. Nonfitting protein-ligand interaction scoring function based on first-principles theoretical chemistry methods: Development and application on kinase inhibitors[J]. http://dx.doi.org/10.1002/jcc.23303,2013.
APA	Rao, Li.,Zhang, Igor Ying.,Guo, Wenping.,Feng, Li.,Meggers, Eric.,...&ERIC MEGGERS.(2013).Nonfitting protein-ligand interaction scoring function based on first-principles theoretical chemistry methods: Development and application on kinase inhibitors.http://dx.doi.org/10.1002/jcc.23303.
MLA	Rao, Li,et al."Nonfitting protein-ligand interaction scoring function based on first-principles theoretical chemistry methods: Development and application on kinase inhibitors".http://dx.doi.org/10.1002/jcc.23303 (2013).