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

by Selleckchem | Nov 21 2023

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.

Comments:

The study you described represents a comprehensive approach in the search for potential anticancer drugs targeting GSK3β. Computational methods, such as docking-based virtual screening, physicochemical analysis, ADMET analysis, and molecular dynamics simulations, have been employed to identify promising compounds from a large library of anti-cancer compounds. The fact that BMS-754807 and GSK429286A emerged as hit compounds with high binding affinities to GSK3β is promising for further experimental validation.

The use of computational techniques in drug discovery has become increasingly important in recent years, as they allow researchers to narrow down the vast chemical space and prioritize compounds for experimental testing. However, it's crucial to note that computational results should always be validated through experimental studies to confirm the actual efficacy and safety of the identified compounds.

If BMS-754807 and GSK429286A prove to be effective and safe in experimental settings, they could potentially pave the way for the development of novel and more targeted cancer therapies. Further research and clinical trials will be necessary to determine their effectiveness in treating specific cancer types and to assess their overall safety profiles in humans. Nonetheless, the findings from this computational study provide a promising starting point for further investigations in the field of cancer drug development.