Computer-aided identification of bioactive compounds from Gongronema latifolium leaf with therapeutic potential against GSK3β, PTB1B and SGLT2

The modulation of certain molecular targets via small-molecule ligands has been regarded as a promising approach for the treatment and management of diabetes-related complications. Notable among these targets are the Glycogen synthase kinase (GSK3β), protein tyrosine phosphatase 1B (PTB1B), and sodium-glucose cotransporter 2 (SGLT2), whose inhibitions have been associated with high prognostic patients with diabetic related complications. However, inhibitors capable of exerting co-modulating effects on the three aforementioned proteins are lacking. Therefore, research aimed at the development of small molecule inhibitors capable of co-targeting these proteins remains unfaltering. Consequently, this study investigated the inhibitory potentials of Gongronema latifolium leaf's compounds against these proteins. Molecular docking was employed to screen 134 compounds against these targets; this gave rise to the identification of ten lead compounds (rutin, epigallocatechin-3-gallate, silymarin, hyperoside, luteolin, baicalin, rosmarinic acid, naringin, butein, and isoorientin) based on their high binding affinities. Subsequently, the toxicity profiles of the compounds were assessed while their bioactivities against the proteins were predicted using 2D quantitative structure-activity relationship (QSAR) models. Furthermore, density functional theory (DFT) calculations were employed to study the reactivity and stability of the aforementioned compounds. Ultimately, toxicity assessment revealed epigallocatechin-3-gallate and butein as the compounds with minimal toxicity, while DFT calculations revealed baicalin, rosmarinic acid, and butein as the most reactive among the lead compounds. Conclusively, this study provides insight into the discovery of phytocompounds with promising inhibitory potential that could facilitate the development of regimens for diabetes management after further in vitro and in vivo studies.