Identifying promising GSK3β inhibitors for cancer management: a computational pipeline combining virtual screening and molecular dynamics simulations

Libo Hua; Farah Anjum; Alaa Shafie; Amal Adnan Ashour; Abdulraheem Ali Almalki; Ali Abdullah Alqarni; Hamsa Jameel Banjer; Sarah Abdullah Almaghrabi; Shan He; Nenggui Xu

doi:10.3389/fchem.2023.1200490

Identifying promising GSK3β inhibitors for cancer management: a computational pipeline combining virtual screening and molecular dynamics simulations

Front Chem. 2023 May 22:11:1200490. doi: 10.3389/fchem.2023.1200490. eCollection 2023.

Authors

Affiliations

¹ South China Research Center for Acupuncture and Moxibustion, Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China.
² Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia.
³ Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, Faculty of Dentistry, Taif University, Taif, Saudi Arabia.
⁴ Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
⁵ Center for Innovations in Personalized Medicine (CIPM), King Abdulaziz University, Jeddah, Saudi Arabia.
⁶ School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan, China.
⁷ Institute for Nano Scale and Technology, College of Science and Engineering, Flinders University, Bedford Park, SA, Australia.
⁸ College of Engineering, Information Technology and Environment, Charles Darwin University, Darwin, NT, Australia.

Abstract

Glycogen synthase kinase-3 (GSK3β), a serine/threonine protein kinase, has been discovered as a novel target for anticancer drugs. Although GSK3β is involved in multiple pathways linked to the etiology of various cancers, no specific GSK3β inhibitor has been authorized for cancer therapy. Most of its inhibitors have toxicity effects therefore, there is a need to develop safe and more potent inhibitors. In this study, a library of 4,222 anti-cancer compounds underwent rigorous computational screening to identify potential candidates for targeting the binding pocket of GSK3β. The screening process involved various stages, including docking-based virtual screening, physicochemical and ADMET analysis, and molecular dynamics simulations. Ultimately, two hit compounds, BMS-754807 and GSK429286A, were identified as having high binding affinities to GSK3β. BMS-754807 and GSK429286A exhibited binding affinities of -11.9, and -9.8 kcal/mol, respectively, which were greater than that of the positive control (-7.6 kcal/mol). Further, molecular dynamics simulations for 100 ns were employed to optimize the interaction between the compounds and GSK3β, and the simulations demonstrated that the interaction was stable and consistent throughout the study. These hits were also anticipated to have good drug-like properties. Finally, this study suggests that BMS-754807 and GSK429286A may undergo experimental validation to evaluate their potential as cancer treatments in clinical settings.

Keywords: cancer; drug-likeness; glycogen synthase kinase-3; molecular dynamics; virtual screening.

Grants and funding

This work was supported by Discipline Collaborative Innovation Team Program of Double First-class and High-level Universities for Guangzhou University of Chinese Medicine—No. 2021XK01.