Novel O-linked β-N-acetylglucosamine Transferase (OGT) Inhibitors from Tinospora Cordifolia: An In-Silico Approach

Abstract

Diabetes mellitus (DM) characterized by excess blood sugar, is a multifactorial metabolic disease that has reached epidemic proportions worldwide. The International Diabetes Foundation (IDF) estimates that approximately 537 million adults will be living with DM in 2021. The total number of people living with DM is projected to rise to 783 million by 2045. According to the absolute or relative lack of insulin signaling, DM is classified into two major forms: Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM). One of the proteins that play a major role in DM is O-linked β-N-acetylglucosamine Transferase (OGT) a glucose-dependent human enzyme that catalyzes the addition of UDP-GlcNAc on the serine and threonine residues of nuclear and cytoplasmic proteins. While this protein plays a vital role in cell cycle regulation and glucose metabolism, an aberration of it could be lethal, and up until now, there have been no reports of small molecule and potent plant-based inhibitors of OGT. In this study, we put molecular docking, ADME/Tox analysis, and MM/GBSA studies to use in identifying novel potent inhibitors of OGT from compounds of Tinospora cordifolia, and we compare our results with that of an established OGT inhibitor, OSMI-1. Based on docking scores and ligand-protein interactions, we predict four (4) top compounds; Apigenin, Bergenin, Diosmetin, and Syringin. In conclusion, the results from the ADME/Tox analysis have led to the prediction that a T. cordifolia compound (Bergenin) has better drug-like characteristics than the standard compound, OSMI-1.