Molecular docking, molecular dynamics, and in vitro studies reveal the potential of angiotensin II receptor blockers to inhibit the COVID-19 main protease
Radwan A. Alnajjar, Ahmed Mostafa, Ahmed Kandeil, Ahmed Ali Al-Karmalawy · Heliyon · 2020
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 (IC 50 = 1.808 μM, and CC 50 = 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.