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Why Are Lopinavir and Ritonavir Effective against the Newly Emerged Coronavirus 2019? Atomistic Insights into the Inhibitory Mechanisms.
Biochemistry. 2020 05 12; 59(18):1769-1779.B

Abstract

Since the emergence of a novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported from Wuhan, China, neither a specific vaccine nor an antiviral drug against SARS-CoV-2 has become available. However, a combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has been found to be effective against SARS-CoV, and both drugs could bind well to the SARS-CoV 3C-like protease (SARS-CoV 3CLpro). In this work, molecular complexation between each inhibitor and SARS-CoV-2 3CLpro was studied using all-atom molecular dynamics simulations, free energy calculations, and pair interaction energy analyses based on MM/PB(GB)SA and FMO-MP2/PCM/6-31G* methods. Both anti-HIV drugs interacted well with the residues at the active site of SARS-CoV-2 3CLpro. Ritonavir showed a somewhat higher number atomic contacts, a somewhat higher binding efficiency, and a somewhat higher number of key binding residues compared to lopinavir, which correspond with the slightly lower water accessibility at the 3CLpro active site. In addition, only ritonavir could interact with the oxyanion hole residues N142 and G143 via the formation of two hydrogen bonds. The interactions in terms of electrostatics, dispersion, and charge transfer played an important role in the drug binding. The obtained results demonstrated how repurposed anti-HIV drugs could be used to combat COVID-19.

Authors+Show Affiliations

Center of Excellence in Computational Chemistry (CECC), Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand.Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand.Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.Center of Excellence in Computational Chemistry (CECC), Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand. Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32293875

Citation

Nutho, Bodee, et al. "Why Are Lopinavir and Ritonavir Effective Against the Newly Emerged Coronavirus 2019? Atomistic Insights Into the Inhibitory Mechanisms." Biochemistry, vol. 59, no. 18, 2020, pp. 1769-1779.
Nutho B, Mahalapbutr P, Hengphasatporn K, et al. Why Are Lopinavir and Ritonavir Effective against the Newly Emerged Coronavirus 2019? Atomistic Insights into the Inhibitory Mechanisms. Biochemistry. 2020;59(18):1769-1779.
Nutho, B., Mahalapbutr, P., Hengphasatporn, K., Pattaranggoon, N. C., Simanon, N., Shigeta, Y., Hannongbua, S., & Rungrotmongkol, T. (2020). Why Are Lopinavir and Ritonavir Effective against the Newly Emerged Coronavirus 2019? Atomistic Insights into the Inhibitory Mechanisms. Biochemistry, 59(18), 1769-1779. https://doi.org/10.1021/acs.biochem.0c00160
Nutho B, et al. Why Are Lopinavir and Ritonavir Effective Against the Newly Emerged Coronavirus 2019? Atomistic Insights Into the Inhibitory Mechanisms. Biochemistry. 2020 05 12;59(18):1769-1779. PubMed PMID: 32293875.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Why Are Lopinavir and Ritonavir Effective against the Newly Emerged Coronavirus 2019? Atomistic Insights into the Inhibitory Mechanisms. AU - Nutho,Bodee, AU - Mahalapbutr,Panupong, AU - Hengphasatporn,Kowit, AU - Pattaranggoon,Nawanwat Chainuwong, AU - Simanon,Nattapon, AU - Shigeta,Yasuteru, AU - Hannongbua,Supot, AU - Rungrotmongkol,Thanyada, Y1 - 2020/04/24/ PY - 2020/4/16/pubmed PY - 2020/5/14/medline PY - 2020/4/16/entrez SP - 1769 EP - 1779 JF - Biochemistry JO - Biochemistry VL - 59 IS - 18 N2 - Since the emergence of a novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported from Wuhan, China, neither a specific vaccine nor an antiviral drug against SARS-CoV-2 has become available. However, a combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has been found to be effective against SARS-CoV, and both drugs could bind well to the SARS-CoV 3C-like protease (SARS-CoV 3CLpro). In this work, molecular complexation between each inhibitor and SARS-CoV-2 3CLpro was studied using all-atom molecular dynamics simulations, free energy calculations, and pair interaction energy analyses based on MM/PB(GB)SA and FMO-MP2/PCM/6-31G* methods. Both anti-HIV drugs interacted well with the residues at the active site of SARS-CoV-2 3CLpro. Ritonavir showed a somewhat higher number atomic contacts, a somewhat higher binding efficiency, and a somewhat higher number of key binding residues compared to lopinavir, which correspond with the slightly lower water accessibility at the 3CLpro active site. In addition, only ritonavir could interact with the oxyanion hole residues N142 and G143 via the formation of two hydrogen bonds. The interactions in terms of electrostatics, dispersion, and charge transfer played an important role in the drug binding. The obtained results demonstrated how repurposed anti-HIV drugs could be used to combat COVID-19. SN - 1520-4995 UR - https://www.unboundmedicine.com/medline/citation/32293875/Why_Are_Lopinavir_and_Ritonavir_Effective_against_the_Newly_Emerged_Coronavirus_2019_Atomistic_Insights_into_the_Inhibitory_Mechanisms_ L2 - https://dx.doi.org/10.1021/acs.biochem.0c00160 DB - PRIME DP - Unbound Medicine ER -