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, 3CL^pro and PL^pro, 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 3CL^pro and PL^pro 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 3CL^pro (ΔG = -7.8 kcal mol^-1), when compared to PL^pro (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.

Supplementary information: The online version contains supplementary material available at 10.1007/s13205-022-03406-w.

Keywords: 3CLpro; Anti-SARS-CoV-2; COVID-19; PLpro; Sitagliptin; iDPP4.

Fig. 1

Synthesis of non-structural proteins (NSPs) and post-translational modification mechanisms of SARS-CoV-2 virus. Stage 1: after recognition of the ACE₂ and/or DPP₄ cell receptors, the viral nucleocapsid is released into the cytoplasm by endocytosis, or fusion of the viral envelope, with the cell membrane. Stage 2: the translation of the pp1a and pp1b genes results in the synthesis of pp1a or pp1ab polyproteins, the latter being generated by a −1 frameshift of ribosomes. These polyproteins are then cleaved by viral 3CL^pro and PL^pro proteases generating 16 virus NSPs, including the RNA-dependent RNA polymerase (RdRp or NSP₁₂)

Fig. 2

Three putative hotspots were detected in the PL^pro receptor (PDB ID: 2FE8) using the CASTp 3.0, FTSite, and FTMap servers. a One cavity, which is the biggest, was called S₁ (green color). b The predicted binding pocket of PL^pro. c and d The 3D and 2D visualizations of the complex stablished by the interaction between PL^pro amino acids and the sitagliptin ligand

Fig. 3

Three putative hotspots were detected in the 3CL^pro receptor (PDB id: 6M2Q) using the CASTp 3.0, FTSite, and FTMap servers. a One cavity, which is the biggest, was called S₁ (magenta color), while the other three smaller cavities were called S₂ (green color), S₃ (salmon color), and S₄ (slate color). b The predicted binding pocket of 3CL^pro. c and d The 3D and 2D visualization and interaction within the amino acids of 3CL^pro and ligand (sitagliptin) complex

Fig. 4

Root-mean-square deviations (RMSD) of the backbone and radius of gyration (R_g) of the proteins from 25 ns long MD trajectory. a and c visualization of RMSD of PL^pro and 3CL^pro uncompleted (blue) and complexed (red). b and d visualization of Rg of PL^pro and 3CL^pro uncompleted (blue) and complexed (red)