Multi-targeted molecular docking, pharmacokinetic analysis, and drug-likeness evaluation of alkaloids for anti-diabetic drug development

Abstract

Diabetes mellitus is a global health challenge, particularly in low-income regions, leading to severe complications. Plant-derived alkaloids offer potential as alternatives to conventional therapies. This study evaluated 31 alkaloids for antidiabetic drug development through molecular docking, pharmacokinetics, and drug-likeness analyses. Four standard drugs (epalrestat, metformin, acarbose, glibenclamide) and four targets (aldose reductase, adenosine monophosphate-activated protein kinase, a-glucosidase, protein tyrosine phosphatase 1B) were used for computational simulations. Molecular docking revealed that alkaloids mahanimbine (-11.5 kcal/mol), echinulin (11.3 kcal/mol), coptisine (-10.9 kcal/mol), and groenlandicine (-9.7 kcal/mol) have substantial binding affinities against aldose reductase compared to epalrestat (-9.3 Kcal/mol). In contrast to metformin (-4.8 kcal/mol), coptisine, echinulin, sanguinarine, and groelandicine showed superior binding affinities against adenosine monophosphateactivated protein kinase. In comparison to acarbose (-8.4 Kcal/mol), coptisine (-9.7 Kcal/mol), sanguinarine (-9.3 Kcal/mol), mahanimbine (-8.9 Kcal/mol), and echinulin (-8.9 Kcal/mol) demonstrated better docking scores against a-glucosidase. Jatrorrhizine, coptisine, sanguinarine, mahanimbine and echinuline respectively demonstrated higher binding scores of 8.8, -7.5, -7.5 and -7.2 Kcal/mol against protein tyrosine phosphatase 1B than glibenclamide (-7.0 Kcal/mol). Most alkaloids adhered to Lipinski’s rule, except casuarine 6-O-a-glucoside and conophylline. Pharmacokinetics identified pinoline as highly bioavailable and central nervous system penetrant, while conophylline had poor bioavailability. The study concluded that alkaloids including mahanimbine, echinulin, coptisine, groenlandicine, sanguinarine, and jatrorrhizine show strong binding affinities and favorable pharmacokinetic properties, requiring further in vitro and in vivo studies for therapeutic validation