Allosteric activation of AMPK ADaM's site by structural analogs of Epigallocatechin and Galegine: computational molecular modeling investigation.

Abstract

5'-Adenosine Monophosphate Protein Kinase (AMPK) is a central protein involved in cellular energy homeostasis, turning on catabolic pathways when the energy level is depleted and inhibiting anabolic pathways utilizing ATP. AMPK is implicated in several diseases including but not limited to diabetes, cancer, and cardiovascular diseases. Regulation of AMPK is cogent for restoring cellular energy levels which mediates the pathways leading to these diseases. Allosteric activation of AMPK via a novel ADaM site is intended for study in this case. In the search for AMPK activators, this study engaged a database for a virtual screening campaign through the ZINC15 database involving pharmacophoric modeling of two reported natural bioactive AMPK activators- Galegine and Epigallocatechin. Generated pharmacophores were targeted against the AMPK-ADaM site by employing various tools within the structure-based drug discovery process among which include consensus molecular docking, physicochemical profiling, ADMET, and molecular dynamics simulation. Advanced methods such as molecular mechanics (MM/GBSA) and quantitative structure-activity relationship (QSAR) were also performed. This investigation revealed promising pharmacophores that show better interactions and pharmacokinetic properties compared to the standards. This study proposes further development of these pharmacophores into potential drugs with better efficacies that could enhance the activation of the AMPK-ADaM site in ameliorating the aforementioned diseases.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00311-x.