Three- and four-body corrected fragment molecular orbital calculations with a novel subdividing fragmentation method applicable to structure-based drug design
Three- and four-body corrected fragment molecular orbital calculations with a novel subdividing fragmentation method applicable to structure-based drug design
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DOI：
10.1016/j.jmgm.2013.01.006
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发表时间：
2013-04-01
影响因子：
2.9
通讯作者：
Nakano, Tatsuya
中科院分区：
文献类型：
--
作者：
Watanabe, Chiduru;Fukuzawa, Kaori;Nakano, Tatsuya
我们发展了一个基于三体和四体修正片段分子轨道(FMO3和FMO4)方法的片段间相互作用能(IFIE)分析方法来评估基于结构的药物设计中官能团单元之间的相互作用。这种新的对配体(以其官能团为单位)和氨基酸残基(以其主链和侧链为单位)的细分碎裂方法使我们能够在不牺牲总能量的化学准确性的情况下更详细地了解配体结合的机理，并使用FMO4方法进行验证。我们用二阶Moller-Plesset微扰理论对雌激素受体(ER)和17β-雌二醇(EST)复合体进行了FMO4计算，并通过FMO4-IFIE分析评估了每个配体结合位点的相互作用。FMO4-IFIE分析表明，当将甾体EST分为“A环”和“D环”两个功能单元时，它们与周围氨基酸残基片段具有亲和力；EST的“A环”与Thr347的主链有极化相互作用，与Glu353和Arg394的侧链有两个氢键；EST的“D环”与His524的侧链有氢键。特别是，在CHPI程序的配合下，很容易确定EST的“A环”与Leu387和Phe404侧链的CH/pi相互作用。FMO4-IFIE分析方法比传统的以配体为单位的IRE分析具有更高的分辨率，每个氨基酸都位于二体近似的框架内，是揭示配体结合机制的有用工具，适用于合理的药物设计，如基于结构的药物设计和基于片段的药物设计。(C)2013 Elsevier Inc.保留所有权利。
We develop an inter-fragment interaction energy (IFIE) analysis based on the three- and four-body corrected fragment molecular orbital (FMO3 and FMO4) method to evaluate the interactions of functional group units in structure-based drug design context. The novel subdividing fragmentation method for a ligand (in units of their functional groups) and amino acid residues (in units of their main and side chains) enables us to understand the ligand-binding mechanism in more detail without sacrificing chemical accuracy of the total energy and IFIEs by using the FMO4 method. We perform FMO4 calculations with the second order Moller-Plesset perturbation theory for an estrogen receptor (ER) and the 17 beta-estradiol (EST) complex using the proposed fragmentation method and assess the interaction for each ligand-binding site by the FMO4-IFIE analysis. When the steroidal EST is divided into two functional units including "A ring" and "D ring", respectively, the FMO4-IFIE analysis reveals their binding affinity with surrounding fragments of the amino acid residues; the "A ring" of EST has polarization interaction with the main chain of Thr347 and two hydrogen bonds with the side chains of Glu353 and Arg394; the "D ring" of EST has a hydrogen bond with the side chain of His524. In particular, the CH/pi interactions of the "A ring" of EST with the side chains of Leu387 and Phe404 are easily identified in cooperation with the CHPI program. The FMO4-IFIE analysis using our novel subdividing fragmentation method, which provides higher resolution than the conventional IRE analysis in units of ligand and each amino acid reside in the framework of two-body approximation, is a useful tool for revealing ligand-binding mechanism and would be applicable to rational drug design such as structure-based drug design and fragment-based drug design. (C) 2013 Elsevier Inc. All rights reserved.