Evaluation of the anti-diabetic drug sitagliptin as a novel attenuate to SARS-CoV-2 evidence-based in silico: molecular docking and molecular dynamics

Abstract

The current outbreak of COVID-19 cases worldwide has been responsible for a significant number of deaths, especially in hospitalized patients suffering from comorbidities, such as obesity, diabetes, hypertension. The disease not only has prompted an interest in the pathophysiology, but also it has propelled a massive race to find new anti-SARS-CoV-2 drugs. In this scenario, known drugs commonly used to treat other diseases have been suggested as alternative or complementary therapeutics. Herein we propose the use of sitagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP4) used to treat type-II diabetes, as an agent to block and inhibit the activity of two proteases, 3CLpro and PLpro, related to the processing of SARS-CoV-2 structural proteins. Inhibition of these proteases may possibly reduce the viral load and infection on the host by hampering the synthesis of new viruses, thus promoting a better outcome. In silico assays consisting in the modeling of the ligand sitagliptin and evaluation of its capacity to interact with 3CLpro and PLpro through the prediction of the ligand bioactivity, molecular docking, overlapping of crystal structures, and molecular dynamic simulations were conducted. The experiments indicate that sitagliptin can interact and bind to both targets. However, this interaction seems to be stronger and more stable to 3CLpro (ΔG = −7.8 kcal mol−1), when compared to PLpro (ΔG = −7.5 kcal mol−1). This study suggests that sitagliptin may be suitable to treat COVID-19 patients, beyond its common use as an anti-diabetic medication. In vivo studies may further support this hypothesis.