Molecular docking, molecular dynamics, and in vitro studies reveal the potential of angiotensin II receptor blockers to inhibit the COVID-19 main protease

Abstract

Drug repurposing is the most rapid and economic way nowadays to rapidly provide effective drugs for our pandemic coronavirus disease 2019 (COVID-19). It was a great debate about ARBs whether to be stopped or continued for patients using them especially at the beginning of the COVID-19 pandemic. In this study, we carried out a virtual screening for almost all members of ARBs (nine) against COVID-19 main protease. Molecular docking as one of the important computational techniques was performed in this work. Interestingly, the tested compounds showed variable binding affinities in the order of N3 inhibitor (10, docked) > Fimasartan (8) > Candesartan (2) > Olmesartan (7) > Azilsartan (9) > Eprosartan (5) > Valsartan (3) > Losartan (1) > Irbesartan (6) > Telmisartan (4). Moreover, Fimasartan (8), Candesartan (2), and Olmesartan (7) were additionally estimated through molecular dynamic simulations monitored via computing the binding free energy using MM-GBSA. The results are promising for rapidly repurposing such drugs (especially, Fimasartan (8) and Candesartan (2)) after further preclinical and clinical studies either alone or in combination with others for the treatment of COVID-19 virus especially known to cause vasodilatation (to prevent blood coagulation) and to reduce inflammation and fibrosis (to prevent pulmonary fibrosis), with well-known safety profiles. In vitro, the virtual findings were consistent with the experimental testing of four representative ARBs. Out of the tested compounds, Olmesartan (7) showed the most promising anti-SARS-CoV-2 activity (IC₅₀ = 1.808 μM, and CC₅₀ = 557.6 μM) with high selectivity index (308.4) against SARS-CoV-2 in Vero E6 cells. This work may clarify and approve not only the safety of ARBs used by a large group of patients worldwide but also their possible effectiveness against the COVID-19 virus either as a prophylactic or treatment option. It intended also to give a clear spot on the structure-activity relationship (SAR) required for the future design of new drugs targeting the newly emerged SARS-CoV-2 protease by medicinal chemists.

Keywords: ARBs; Biological sciences; COVID-19; Chemistry; Computer science; Docking; Drug repurposing; In vitro studies; MD; MM-GBSA; Materials science; Physics.

Figure 1

Drug repurposing of ARBs as COVID-19 inhibitors especially causing V.D. and preventing inflammation and fibrosis characteristic to pandemic infection.

Figure 2

Chemical structures of Losartan 1, Candesartan 2, Valsartan 3, Telmisartan 4, Eprosartan 5, Irbesartan 6, Olmesartan 7, Fimasartan 8, Azilsartan 9 and N3 10.

Figure 3

Plots of RMSD for Cα atoms (Å) concerning the initial structure vs simulation time (ns) for all the complexes.

Figure 4

Plots of RMSD for ligand atoms (Å) concerning the initial structure vs simulation time (ns) of all the complexes.

Figure 5

Plots of RMSD for Olmesartan atoms (Å) concerning the initial structure vs simulation time (ns) for all the complexes.

Figure 6

The aligned structures of Ligands-6LU7 during simulation; green 0 ns, yellow 75 ns, red 150 ns.

Figure 7

The histogram of a) Fimasartan-6LU7, b) Candesartan-6LU7, and c) Olmesartan-6LU7 contact throughout the trajectory.

Figure 8

Fimasartan- 6LU7, Candesartan- 6LU7, and Olmesartan - 6LU7 interactions shown in each trajectory frame by the active site amino acids, zero interaction are represented by white while more interactions by the deep color.

Figure 9

Dose-response curves for the tested drugs in Vero-E6 cells. Various dilutions of the drugs were applied to the 90% confluent cell monolayers and assayed after 72 h to determine the CC₅₀ (half-maximal cytotoxic concentrations) or IC₅₀ (half-maximal inhibitory concentrations). Nonlinear regression analysis of GraphPad Prism software (version 5.01) was used to calculate CC₅₀ and IC₅₀ by plotting log inhibitor versus normalized response (variable slope).