title: Using docking and alchemical free energy approach to determine the binding mechanism of eEF2K inhibitors and prioritizing the compound synthesis.
abstract: A-484954 is a known eEF2K inhibitor with submicromolar IC50 potency. However, the binding mechanism and the crystal structure of the kinase remains unknown. Here, we employ a homology eEF2K model, docking and alchemical free energy simulations to probe the binding mechanism of eEF2K, and in turn, guide the optimization of potential lead compounds. The inhibitor was docked into the ATP-binding site of a homology model first. Three different binding poses, hypothesis 1, 2, and 3, were obtained and subsequently applied to molecular dynamics (MD) based alchemical free energy simulations. The calculated relative binding free energy of the analogs of A-484954 using the binding pose of hypothesis 1 show a good correlation with the experimental IC50 values, yielding an r (2) coefficient of 0.96 after removing an outlier (compound 5). Calculations using another two poses show little correlation with experimental data, (r (2) of less than 0.5 with or without removing any outliers). Based on hypothesis 1, the calculated relative free energy suggests that bigger cyclic groups, at R1 e.g., cyclobutyl and cyclopentyl promote more favorable binding than smaller groups, such as cyclopropyl and hydrogen. Moreover, this study also demonstrates the ability of the alchemical free energy approach in combination with docking and homology modeling to prioritize compound synthesis. This can be an effective means of facilitating structure-based drug design when crystal structures are not available.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin Austin, TX, USA ; Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin Austin, TX, USA.
authors.forename: Qiantao
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin Austin, TX, USA.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Edupuganti
authors.affiliation: Graduate Program in Cell and Molecular Biology, The University of Texas at Austin Austin, TX, USA.
authors.forename: Clint D J
authors.initials: CD
authors.lastname: Tavares
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin Austin, TX, USA ; Graduate Program in Cell and Molecular Biology, The University of Texas at Austin Austin, TX, USA.
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Dalby
authors.affiliation: Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin Austin, TX, USA.
authors.forename: Pengyu
authors.initials: P
authors.lastname: Ren
keywords: docking; drug discovery; eEF2K inhibitor; free energy calculation; kinase; molecular dynamics