Graphical abstract Highlights • Novel analogues of arbidol (Umifenovir) were designed by scaffold morphing approach. • Top hits subjected to docking based virtual screening against SARS-CoV-2 targets. • Fifteen analoges demonstrated good results in-silico with optimum ADME properties. • A_BR18 and A_BR28 displayed multi-targeting potential in COVID-19. 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.
【저자키워드】 COVID-19, SARS-CoV-2, Arbidol, molecular docking, ADME, Scaffold morphing, TMPRSS2, 【초록키워드】 ACE2, clinical trial, furin, Influenza virus, Virtual screening, 3CLpro, docking, protease, virus, binding affinity, Novel coronavirus, Spread, Epidemic, therapeutic, membrane fusion, targets, receptor, molecular, novel, in-silico, inhibitor, interactions, Interaction, Invasion, health emergency, SARS-coronavirus, Abstract, enzyme, residue, Compound, transmembrane, host protease, docking score, SARS-CoV-2 SP, analogue, replication of SARS-CoV-2, serine 2, approach, limit, other proteases, Wuhan, China, predicted, involved, reported, approved, exhibited, demonstrated, the SARS-CoV-2, 【제목키워드】 ACE2, therapy, umifenovir, Interaction, involved, other protease,