RESEARCH ARTICLE


Comparative Docking Assessment of Glucokinase Interactions with its Allosteric Activators



Vandana Kumari, Chenglong Li*
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, OH 43210, USA


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© Kumari and Li; Licensee Bentham Open

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, OH 43210, USA; Tel: 614-247-8786; Fax: 614-292-2435; E-mail: li.728@osu.edu


Abstract

Glucokinase (GK) is expressed in multiple organs and plays a key role in hepatic glucose metabolism and pancreatic insulin secretion. GK could indeed serve as pacemaker of glycolysis and could be an attractive target for type 2 diabetes (T2D). The recent preclinical data of first GK activator RO-28-1675 has opened up a new field of GK activation as a powerful tool in T2D therapies. The GK allosteric site is located ~20Å away from glucose binding site. Chemical structure of Glucokinase activators (GKA) includes three chemical arms; all consisting of cyclic moiety and joined in a shape resembling the letter Y. In this study, comparative docking assessment using Autodock4 revealed that the three arms bind to three aromatic/hydrophobic subpockets at the allosteric site. Our dockings have overall consistency with experimental data in both docking modes and simulated binding free energies, and offer insights on understanding GK/GKA interactions and further GKA design. Specifically, for the first pocket, involvement of Arg63 as key residue in two specific hydrogen-bond formations with all allosteric activators defines the binding feature; for the second pocket, it has the most diverse binding interactions, mostly aromatic, hydrophobic and multiple hydrogen bonds. The site has the best potential for further GKA optimization by utilizing aromatic heterocycles and hydrogen bond forming linkers to build the GKA 2nd arm.

Keywords: Molecular docking, Molecular recognition, Free energy, AutoDock, glucokinase, GKA, Glucokinase activator, Allosteric, Drug design.