Repurposing of FDA-approved Drugs Identifies Glipizide as a Potent HMG-CoA Reductase Inhibitor: a High-Throughput Virtual Screening and Molecular Dynamics Approach for Targeting Hypercholesterolemia

Abstract Purpose Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of mortality worldwide. Several inhibitors of 3 -hydroxy- 3 -methylglutaryl-CoA reductase (HMG-R), the key hepatic cholesterogenic enzyme, are prescribed to treat hypercholesterolemia and ASCVD. Statins, the established HMG-R inhibitors, exhibit promising cholesterol-lowering effects; however, their long-term use has prompted significant concerns, necessitating the search for additional therapeutic candidates with strong HMG-R inhibitory activity. Therefore, this study aims to find potential HMG-R inhibitor/s that may help reduce excess cholesterol levels via targeting HMG-R activity. Methods In this study, 1285 FDA-approved small molecules were assessed for their HMG-R inhibitory potential using high-throughput virtual screening (HTVS) and molecular docking simulations (MDS). Results Based on lowest binding energies and favourable docking interactions, seven compounds were selected for further studies. These compounds satisfied the Lipinski’s rules, ADME, and toxicity evaluations. Computational molecular informatics analysis revealed that all screened compounds efficiently occupied the catalytic domain of HMG-R, with binding energy (∆G) ranging from − 5.82 to -7.73 kcal/mol. In contrast, amongst other compounds, glipizide showed the lowest ∆G (-7.73 kcal/mol), surpassing the ∆G of the substrate HMG-CoA and standard drug atorvastatin (-3.99 and − 4.22 kcal/mol, respectively). A 100 ns MDS demonstrated that glipizide exhibited better stability compared with atorvastatin. Molecular mechanical-generalized Born surface area (MM-GBSA) analysis further showed that free ∆G of glipizide (-21.59 kcal/mol) was better than that of atorvastatin (-18.05 kcal/mol). Conclusion In conclusion, as an FDA-approved antidiabetic drug, glipizide may be used for managing patients with both diabetes and hyperlipidaemia by additionally targeting human HMG-R.