Are losartan and imatinib effective against SARS-CoV2 pathogenesis? A pathophysiologic-based in silico study

Abstract

Proposing a theory about the pathophysiology of cytokine storm in COVID19, we were to find the potential drugs to treat this disease and to find any effect of these drugs on the virus infectivity through an in silico study. COVID-19-induced ARDS is linked to a cytokine storm phenomenon not explainable solely by the virus infectivity. Knowing that ACE2, the hydrolyzing enzyme of AngII and SARS-CoV2 receptor, downregulates when the virus enters the host cells, we hypothesize that hyperacute AngII upregulation is the eliciting factor of this ARDS. We were to validate this theory through reviewing previous studies to figure out the role of overzealous activation of AT1R in ARDS. According to this theory losartan may attenuate ARDS in this disease. Imatinib, has previously been elucidated to be promising in modulating lung inflammatory reactions and virus infectivity in SARS and MERS. We did an in silico study to uncover any probable other unconsidered inhibitory effects of losartan and imatinib against SARS-CoV2 pathogenesis. Reviewing the literature, we could find that over-activation of AT1R could explain precisely the mechanism of cytokine storm in COVID19. Our in silico study revealed that losartan and imatinib could probably: (1) decline SARS-CoV2 affinity to ACE2. (2) inhibit the main protease and furin, (3) disturb papain-like protease and p38MAPK functions. Our reviewing on renin-angiotensin system showed that overzealous activation of AT1R by hyper-acute excess of AngII due to acute downregulation of ACE2 by SARS-CoV2 explains precisely the mechanism of cytokine storm in COVID-19. Besides, based on our in silico study we concluded that losartan and imatinib are promising in COVID19.

Keywords: Cytokine storm; Imatinib; Losartan; Main protease; Papain-like protease; SARS-CoV2.

Fig. 1

a SARS-CoV2-ACE2 complex. b 1-Im,nACE2, 2-super-imposition of ACE2 and Im,nACE2, 3-super-imposition of α-helix of ACE2 and Im,nACE2. c 1-Lo,nACE2, 2-super-imposition of ACE2 and Lo.nACE2, 3-super-imposition of α-helix of ACE2 and Lo,nACE2. d Hydrophobic and hydrogen bonds of SARS-CoV2RBD-ACE2

Fig. 2

Main Protease (Mpro) of SARS-CoV2 complex with imatinib and losartan. a Ribbon view of complex and Poseview of interaction with imatinib. b Ribbon view of complex and Poseview of interaction with losartan

Fig. 3

Position of Imatinib and Losartan in complex with furin with PDBID: 6hzb after Docking simulation. a Ribbon view of complex and Poseview of interaction with imatinib. b Ribbon view of complex and Poseview of interaction with Losartan

Fig. 4

Position of Imatinib and losartan in complex with p38MAPK with PDBID: 1a9u after Docking simulation. a Ribbon view of complex and Poseview of interaction with imatinib. b Ribbon view of complex and Poseview of interaction with Losartan

Fig. 5

Position of Imatinib and Losartan in complex with PLpro with PDBID: 3mj5, before and after 100 ns MD simulation and redocking. a Ribbon and poseview of complex of PLpro with imatinib before 100 ns MD simulation, b ribbon and poseview of complex PLpro with imatinib after 100 ns MD simulation. c Ribbon and poseview of complex of PLpro with losartan before 100 ns MD simulation, d ribbon and poseview of complex PLpro with losartan after 100 ns MD simulation

Fig. 6

Diagrams of Losartan-PLpro and Imatinib-PLpro complexes after 100 ns MD simulation. a RMSD; b Rg; c RMSF; d H-Bonding

Fig. 7

Spiral lung CT-scan of a 50 years old patient with COVID19; a Apr 6, 2020; b Apr 10, 2020