Improving the Accuracy of Protein-Ligand Binding Mode Prediction Using a Molecular Dynamics-Based Pocket Generation Approach

被引：8

作者：

Araki, Mitsugu ^{[1
,2
]}

Iwata, Hiroaki ^{[1
,3
]}

Ma, Biao ^{[3
]}

Fujita, Atsuto ^{[3
]}

Terayama, Kei ^{[4
,6
]}

Sagae, Yukari ^{[1
]}

Ono, Fumie ^{[1
]}

Tsuda, Koji ^{[4
]}

Kamiya, Narutoshi ^{[5
]}

Okuno, Yasushi ^{[1
,2
]}

机构：

[1] Kyoto Univ, Grad Sch Med, Sakyo Ku, 53 Shogoin Kawaharacho, Kyoto 6068507, Japan

[2] RIKEN, Adv Inst Computat Sci, Chuo Ku, 7-1-26 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan

[3] FBRI, Res & Dev Grp Silico Drug Discovery, Procluster Kobe, Chuo Ku, 6-3-5 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan

[4] Univ Tokyo, Dept Computat Biol & Med Sci, Grad Sch Frontier Sci, Chiba 2778561, Japan

[5] Univ Hyogo, Grad Sch Simulat Studies, Chuo Ku, 7-1-28 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan

[6] RIKEN, Ctr Adv Intelligence Project, Chuo Ku, 1-4-1 Nihombashi, Tokyo 1030027, Japan

来源：

JOURNAL OF COMPUTATIONAL CHEMISTRY | 2018年 / 39卷 / 32期

关键词：

protein; in-silico drug discovery; molecular docking; molecular dynamics simulation; the binding free energy; CDK2 INHIBITORS PREDICTION; FREE-ENERGIES; AUTOMATED DOCKING; ENSEMBLE DOCKING; STRUCTURAL BASIS; SIMULATIONS; VALIDATION; INSIGHTS; RECEPTOR; POTENCY;

D O I：

10.1002/jcc.25715

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Protein-drug binding mode prediction from the apo-protein structure is challenging because drug binding often induces significant protein conformational changes. Here, the authors report a computational workflow that incorporates a novel pocket generation method. First, the closed protein pocket is expanded by repeatedly filling virtual atoms during molecular dynamics (MD) simulations. Second, after ligand docking toward the prepared pocket structures, binding mode candidates are ranked by MD/Molecular Mechanics Poisson-Boltzmann Surface Area. The authors validated our workflow using CDK2 kinase, which has an especially-closed ATP-binding pocket in the apo-form, and several inhibitors. The crystallographic pose coincided with the top-ranked docking pose for 59% (34/58) of the compounds and was within the top five-ranked ones for 88% (51/58), while those estimated by a conventional prediction protocol were 9% (5/58) and 50% (29/58), respectively. Our study demonstrates that the prediction accuracy is significantly improved by preceding pocket expansion, leading to generation of conformationally-diverse binding mode candidates. (c) 2018 Wiley Periodicals, Inc.

引用

页码：2679 / 2689

页数：11

共 59 条

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