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Improving the Accuracy of Protein‐Ligand Binding Mode Prediction Using a Molecular Dynamics‐Based Pocket Generation Approach
Author(s) -
Araki Mitsugu,
Iwata Hiroaki,
Ma Biao,
Fujita Atsuto,
Terayama Kei,
Sagae Yukari,
Ono Fumie,
Tsuda Koji,
Kamiya Narutoshi,
Okuno Yasushi
Publication year - 2018
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.25715
Subject(s) - molecular dynamics , docking (animal) , virtual screening , protein–ligand docking , workflow , chemistry , binding pocket , binding site , computational biology , computational chemistry , computer science , database , biochemistry , biology , medicine , nursing
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. © 2018 Wiley Periodicals, Inc.