Antidiabetic potency and molecular insights of natural products bearing indole moiety: A systematic bioinformatics investigation targeting AKT1

Abstract

Diabetic mellitus (DM) is a chronic disorder, and type 2 DM (T2DM) is the most prevalent among all categories (nearly 90%) across the globe every year. With the availability of potential drugs, the prevalence rate has remained uncontrollable, while natural resources showed a promising potency, and exploring such potential candidates at the preclinical stage is essential. An extensive literature search selected 89 marine and plant-derived indole derivatives with anti-inflammatory, antioxidant, lipid-lowering, etc., activities. However, as we know, drugs have not been able to convert from ’lead’ to 'mainstream' due to inadequate drug-ability profiles, as our systematic investigation proved and selected herdmanine_A (HERD_A) and penerpene_D (PENE_D) as the most potential antidiabetic candidates from the library of indole derivatives. Based on our previous network pharmacology study, we selected three new target enzymes: Acetyl-CoA carboxylase 2 (ACACB; PDB ID: 3JRX), cyclin-dependent kinase 4 (CDK4; PDB ID: 3G33), and alpha serine/threonine-protein kinase 1 (AKT1; PDB ID: 3O96) to assess the antidiabetic potency of selected indole derivatives through binding energy or docking score. To conduct molecular docking studies with these enzymes, we used the PyRx-AutoDock platform. Furthermore, molecular dynamic simulation at 100 ns, physicochemical analysis, pharmacokinetics, toxicity assessment, and drug-likeness evaluation suggested that HERD_A and penerpene PENE_D were the most potent inhibitors against AKT1 compared to koenimbine (most potential based on the recorded IC50 value) and murrayakonine_A (most potential based on the docking score). In summary, HERD_A and/or PENE_D have the potential to be used as alternative therapeutic agent for the treatment of diabetes after some pharmacological investigation.