The potential effects of clinical antidiabetic agents on SARS-CoV-2

Abstract

Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is currently posing significant threats to public health worldwide. It is notable that a substantial proportion of patients with sever COVID-19 have coexisting diabetic conditions, indicating the progression and outcome of COVID-19 may relate to diabetes. However, it is still unclear whether diabetic treatment principles can be used for the treatment of COVID-19.

Methods: We conducted a computational approach to screen all commonly used clinical oral hypoglycemic drugs to identify the potential inhibitors for the main protease (M^pro ) of SARS-CoV-2, which is one of the key drug targets for anti-COVID-19 drug discovery.

Results: Six antidiabetic drugs with docking scores higher than 8.0 (cutoff value), including repaglinide, canagliflozin, glipizide, gliquidone, glimepiride, and linagliptin, were predicted as the promising inhibitors of M^pro . Interestingly, repaglinide, one of the six antidiabetic drugs with the highest docking score for M^pro , was similar to a previously predicted active molecule nelfinavir, which is a potential anti-HIV and anti-COVID-19 drug. Moreover, we found repaglinide shared similar docking pose and pharmacophores with a reported ligand (N3 inhibitor) and nelfinavir, demonstrating that repaglinide would interact with M^pro in a similar way.

Conclusion: These results indicated that these six antidiabetic drugs may have an extra effect on the treatment of COVID-19, although further studies are necessary to confirm these findings.

Keywords: COVID-19; SARS-CoV-2; antidiabetic agents; diabetes; 新型冠状病毒。; 新型冠状病毒肺炎; 糖尿病; 降糖药物.

FIGURE 1

Molecular dynamics study to explore the binding pocket of M^pro. A, The crystal structure superimposed on the last configuration after 200 ns of simulation for M^pro and N3 inhibitor. The initial and the last configurations were shown in green and magenta, respectively. B, The root‐mean‐square deviation (RMSD) of M^pro and N3 inhibitor. C,)Binding free energy decomposition of M^pro and N3 inhibitor system. D, The key residues for the binding interaction of M^pro and N3 inhibitor and the binding pocket of M^pro

FIGURE 2

Prediction of the potential ligands for M^pro. The docking mode of M^pro and repaglinide, canagliflozin, glimepiride, glipizide, gliquidone, and linagliptin, respectively

FIGURE 3

The pharmacophores and binding poses with M^pro, as well as the effect on angiotensin‐converting enzyme 2 (ACE2) expression of indicated drugs. A, The structure and pharmacophores of N3 inhibitor, nelfinavir, and repaglinide. B, The binding conformations of N3 inhibitor (crystal structure), nelfinavir, and repaglinide with the pocket. C and D, A549 and human umbilical vein endothelial cells (HUVEC) cells were treated by repaglinide (2 μM), canagliflozin (50 μM), glimepiride (50 μM), glipizide (50 μM), gliquidone (50 μM), and linagliptin (50 nM) respectively for 2 hours, the mRNA (C) and protein (D) expressions of ACE2 were assessed by quantitative real‐time polymerase chain reaction and immunoblotting. n = 3 independent studies for (C) and (D). Data are presented as means ± SEM. n.s., not significant compared with control