Aldose reductase (AR) is a rate-limiting metabolic enzyme in the polyol pathway which reduces glucose to sorbitol in insulin-independent tissues like the heart, liver, kidney, retina, RBC, and brain. This reaction takes place enormously during hyperglycemia, resulting in sorbitol buildup in these tissues contributing to microvascular complications. Diverse AR inhibitors (ARIs) emerged as therapeutic agents to prevent or minimize these complications which grabbed global attention. In an attempt to explore new ARI compounds, we considered 30 diverse sets of reported ARIs as query models and procured a total of 418 hit compounds from the ZINCPharmer database. Absorption, distribution, metabolism, excretion, and toxicity Absorption, distribution, metabolism, excretion, and toxicity screening of all these compounds has been performed using computational tools like SwissADME, ADMETLab2.0, PreADMET, and ProTox-II which resulted in 70 potential hits that were further scrutinized by in silico docking analysis (AutoDock4.2). The docked protein-ligand interactions were visualized by employing BIOVIA Discovery Studio and AutoDock softwares. Amongst the 70 ZINC IDs, compound ZINC89259516 (Butein pharmacophore) exhibited strong affinity to AR and displayed the least binding energy (BE) of −11.57 kcal/mol with key amino acid interactions being Trp111, Asn160, Cys298, Trp20, Val47, Tyr48, Trp79, Tyr209, Pro211, Ile260, and Lys262 in the binding pocket of AR. This was followed by Benzylisoquinoline pharmacophore ZINC13349982 which showed the BE of −11.48 kcal/mol interacting with amino acid residues Cys303 and hydrophobic interactions with Trp20, Tyr48, Trp79, His110, Trp111, Tyr209, Pro211, Leu212, Pro215, Lys262, and Leu300. Overall, the present in silico results revealed that the leading compounds ZINC89259516 and ZINC13349982 were ascertained to be safe and promising therapeutic drug candidates based on favorable ADME profile, good oral bioavailability and also being non-toxic. These two molecules pose as suitable drug-like ARIs which could be further investigated by in vitro and in vivo studies to provide a clear insight into treating long-term diabetic complications.
Key words: Diabetes, Aldose Reductase, Docking, ADME, ProTox, Inhibitor
|
