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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.
Virus Res. 2020 11; 289:198146.VR

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.

Authors+Show Affiliations

Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India.Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India. Electronic address: omsilakari@gmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32866534

Citation

Choudhary, Shalki, and Om Silakari. "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." Virus Research, vol. 289, 2020, p. 198146.
Choudhary S, Silakari O. 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. Virus Res. 2020;289:198146.
Choudhary, S., & Silakari, O. (2020). 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. Virus Research, 289, 198146. https://doi.org/10.1016/j.virusres.2020.198146
Choudhary S, Silakari O. 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. Virus Res. 2020;289:198146. PubMed PMID: 32866534.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Choudhary,Shalki, AU - Silakari,Om, Y1 - 2020/08/29/ PY - 2020/07/10/received PY - 2020/08/24/revised PY - 2020/08/26/accepted PY - 2020/9/1/pubmed PY - 2020/10/31/medline PY - 2020/9/1/entrez KW - ADME KW - Arbidol KW - COVID-19 KW - Molecular docking KW - SARS-CoV-2 KW - Scaffold morphing SP - 198146 EP - 198146 JF - Virus research JO - Virus Res VL - 289 N2 - 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. SN - 1872-7492 UR - https://www.unboundmedicine.com/medline/citation/32866534/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-1702(20)31053-4 DB - PRIME DP - Unbound Medicine ER -