In silico design and computational screening of berberine derivatives for potential antidiabetic activity through allosteric activation of the AMPK pathway.

Globally, there is an increase in the prevalence of metabolic illnesses, including diabetes mellitus. However, current therapies for diabetes and other metabolic illnesses are not well understood. Pharmacological treatment of type 2 diabetes is challenging, moreover, the majority of antidiabetic medications are incompatible with individuals who have cardiac disease, renal illness, or liver damage. Despite the ongoing development of innovative medicines, the quest for an optimal treatment that serves both as a hypoglycaemic agent and mitigates diabetes-related problems remains unattained. Recent research demonstrates that berberine has significant promise in the treatment of diabetes. Berberine influences glucose metabolism by enhancing insulin secretion, promoting glycolysis, decreasing adipogenesis, disrupting the function of the mitochondria, stimulating the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway, thereby augmenting glucokinase activity. In this study, we virtually designed and synthesized 5 berberine derivatives (data not yet published) to study their impact on the AMP-activated protein kinase (AMPK) pathway through molecular docking and dynamic simulation study. Activation of AMPK plays an important role by enhancing glucose uptake in cells. Berberine and its derivatives showed potential for allosteric activation of the AMPK pathway. The allosteric activation of AMPK α- & β-subunit involves complex interactions with standard activators like A-769662. Berberine and its derivatives showed potential binding affinity at the allosteric site of AMPK α- & β-subunit, forming similar interactions to A-769662. Molecular dynamic simulations indicated stability of these complexes. However, interactions of these derivatives with the AMPK γ-subunit were less stable, suggesting limited potential for allosteric activation at this site. Further studies are required to assess the long-term stability and efficacy of berberine and its derivatives as allosteric AMPK activators. Additionally, ADMET predictions suggest these derivatives to be safe, warranting further experimental and preclinical investigations as potential antidiabetic agents. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00295-0.