Title

Pharmacophore feature-based virtual screening for finding potent GSK-3 inhibitors using molecular docking and dynamics simulations

Authors

Navneet Chauhan1*, Anuradha Gajjar2, Syed Hussain Basha3

Affiliation

1Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382 481, Gujarat, India; 2Department of Pharmaceutical Chemistry, Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, Changa 388 421, Gujarat, India; 3Innovative Informatica Technologies, Hyderabad 500 049, Telangana, India

Email

Navneet Chauhan - E-mail: navneetscientific@gmail.com; Mob: +91-8511255395; *Corresponding author

Article Type

Hypothesis

Date

Received November 9, 2016; Accepted November 21, 2016; Published November 30, 2016

Glycogen synthase kinase-3 (GSK-3) is a multitasking serine/threonine protein kinase, which is associated with the pathophysiology of several diseases such as diabetes, cancer, psychiatric and neurodegenerative diseases. Tideglusib is a potent, selective, and irreversible GSK-3 inhibitor that has been investigated in phase II clinical trials for the treatment of progressive supranuclear palsy and Alzheimer's disease. In the present study, we performed pharmaco-phore feature-based virtual screening for identifying potent target specific GSK-3 inhibitors. We found 64 compounds that show better GSK-3 binding potentials compared with those of Tideglusib. We further validated the obtained binding potentials by performing 20-ns molecular dynamics simulations for GSK-3 complexed with Tideglusib and with the best compound found via virtual screening in this study. Several interesting molecular-level interactions were identified, including a covalent interaction with Cys199 residue at the entrance of the GSK-3 active site. These findings are expected to play a crucial role in the binding of target-specific GSK-3 inhibitors.

Keywords:

Docking, GSK-3, Molecular dynamics, Tideglusib, Virtual screening.

Citation

Chauhan et al. Bioinformation 12(10): 391-395 (2016)

Edited by

P Kangueane

ISSN

0973-2063

Publisher

Biomedical Informatics

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.