Scaffold morphing of arbidol (umifenovir) in search of multi-targeting therapy halting the interaction of SARS-CoV-2 with ACE2 and other proteases involved in COVID-19

Abstract

The rapid emergence of novel coronavirus, SARS-coronavirus 2 (SARS-CoV-2), originated from Wuhan, China, imposed a global health emergency. Angiotensin-converting enzyme 2 (ACE2) receptor serves as an entry point for this deadly virus while the proteases like furin, transmembrane protease serine 2 (TMPRSS2) and 3 chymotrypsin-like protease (3CLpro) are involved in the further processing and replication of SARS-CoV-2. The interaction of SP with ACE2 and these proteases results in the SARS-CoV-2 invasion and fast epidemic spread. The small molecular inhibitors are reported to limit the interaction of SP with ACE2 and other proteases. Arbidol, a membrane fusion inhibitor approved for influenza virus is currently undergoing clinical trials against COVID-19. In this context, we report some analogues of arbidol designed by scaffold morphing and structure-based designing approaches with a superior therapeutic profile. The representative compounds A_BR4, A_BR9, A_BR18, A_BR22 and A_BR28 restricted the interaction of SARS-CoV-2 SP with ACE2 and host proteases furin and TMPRSS2. For 3CLPro, Compounds A_BR5, A_BR6, A_BR9 and A_BR18 exhibited high binding affinity, docking score and key residue interactions. Overall, A_BR18 and A_BR28 demonstrated multi-targeting potential against all the targets. Among these top-scoring molecules A_BR9, A_BR18, A_BR22 and A_BR28 were predicted to confer favorable ADME properties.

Keywords: ADME; Arbidol; COVID-19; Molecular docking; SARS-CoV-2; Scaffold morphing.

Graphical abstract

Fig. 1

Proposed mechanism showing the interaction of spike protein with ACE2 and other proteases.

Fig. 2

Six different bio-isosteric replacement sites of arbidol and corresponding hits found effective against SARS-CoV-2-ACE2 complex, furin and TMPRSS2 in preventing viral attachment to the host cell.

Fig. 3

Six different bio-isosteric replacement sites of arbidol and corresponding hits found effective against main protease 3CLPro in preventing viral replication.

Fig. 4

Contact summary of best hits; A_BR4 (A) and A_BR18 (B) and A_BR28 with the active site of ACE2.

Fig. 5

Contact summary of best hits; A_BR9 (A), A_BR18 (B) and A_BR28 (C) with the active site of SARS-CoV-2 SP.

Fig. 6

Contact summary of best hits; A_BR18 (A), A_BR28 (B) and A_BR34 (C) with the active site of furin.

Fig. 7

Contact summary of best hits; A_BR17 (A), A_BR22 (B), A_BR28 (C) with the active site of TMPRSS2.

Fig. 8

3D view showing docked complex of A_BR18 with ACE2 (A), SARS-CoV-2 spike protein (B) and furin (C); ligand shown in yellow and interacting residues are shown in pink.

Fig. 9

3D view showing docked complex of A_BR22 with furin (A) and TMPRSS2 (B) proteases; ligand shown in yellow and interacting residues are shown in pink.

Fig. 10

3D view of docked complex of A_BR34 with furin; ligand shown in yellow and interacting residues are shown in pink.

Fig. 11

3D view showing docked complex of A_BR28 with ACE2 (A), SARS-CoV-2 spike protein (B), furin (C) and TMPRSS2 (D); ligand shown in yellow and interacting residues are shown in pink.

Fig. 12

Contact summary of best hits; A_BR5 (A), A_BR9 (B), A_BR18 (C) with the active site of 3CLPro.

Fig. 13

3D view showing docked complex of best hits A_BR5 (A), A_BR6 (B), A_BR9 (C) and A_BR18 (D) with main protease 3CLPro; ligand shown in yellow and interacting residues are shown in pink.