title: The Effect of Conformational Flexibility on Binding Free Energy Estimation between Kinases and Their Inhibitors.
abstract: Accurate prediction of binding affinities of drug candidates to their targets remains challenging because of protein flexibility in solution. Conformational flexibility of the ATP-binding site in the CDK2 and ERK2 kinases was identified using molecular dynamics simulations. The binding free energy (ΔG) of twenty-four ATP-competitive inhibitors toward these kinases was assessed using an alchemical free energy perturbation method, MP-CAFEE. However, large calculation errors of 2-3 kcal/mol were observed using this method, where the free energy simulation starts from a single equilibrated conformation. Here, we developed a new ΔG computation method, where the starting structure was set to multiconformations to cover flexibility. The calculation accuracy was successfully improved, especially for larger molecular size compounds, leading to reliable prediction of a broader range of drug candidates. The present study demonstrates that conformational flexibility of interactions between a compound and the glycine-rich loop in the kinases is a key factor in ΔG estimation.
authors.affiliation: RIKEN Advanced Institute for Computational Science, 7-1-26 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Araki
authors.affiliation: RIKEN Advanced Institute for Computational Science, 7-1-26 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.|Graduate School of Simulation Studies, University of Hyogo , 7-1-28 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Narutoshi
authors.initials: N
authors.lastname: Kamiya
authors.affiliation: Mitsui Knowledge Industry Co., Ltd., 2-5-1 Atago, Minato-ku, Tokyo 105-6215, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Sato
authors.affiliation: RIKEN Advanced Institute for Computational Science, 7-1-26 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.|Graduate School of Medicine, Kyoto University , 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nakatsui
authors.affiliation: Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST) , 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.|Division of Biomedical Science, Faculty of Medicine, University of Tsukuba , 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Hirokawa
authors.affiliation: RIKEN Advanced Institute for Computational Science, 7-1-26 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.|Graduate School of Medicine, Kyoto University , 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okuno
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1