Novel hits for targeting kidney failure in type 2 diabetes derived via in silico screening of the ZINC natural product database

Renal dysfunction is a common and potentially fatal consequence often noticed in persons who have been diagnosed with type 2 diabetes mellitus (T2DM). The gravity of this complication is underscored by the heightened likelihood of death linked to its advancement. Therefore, it is crucial to prioritize the prevention of the progress of renal impairment. The efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in retarding the advancement of renal dysfunction and albuminuria has been demonstrated, underscoring their potential utility in the management of renal problems. In a quest to unearth natural SGLT2 inhibitors, a comprehensive study was undertaken, encompassing structure-based virtual screening and a range of tools deployed to separate through the extensive ZINC database. Through the application of a pharmacophore model, a cohort of 11,336 natural compounds were discerned from the ZINC database that could potentially serve as SGLT2 inhibitors. Amid this collection, two compounds were singled out via a rigorous assessment of ADME (absorption, distribution, metabolism, and excretion) attributes, oral bioavailability, molecular dynamics parameters, and akin docking affinities to approved inhibitors. Compound 580 emerged as a promising candidate, validated by its congruence with metabolic processes and the absence of proclivities toward cardiotoxic effects. The findings from this investigation serve to reinforce the validation of SGLT2 inhibitors, thus paving the way for comprehensive in vitro and in vivo experimentation. Concurrently, these outcomes act as a catalyst for the innovation of novel inhibitors, heralding a new era of possibilities.