Identification of saquinavir as a potent inhibitor of dimeric SARS-CoV2 main protease through MM/GBSA
- PDF / 1,998,780 Bytes
- 11 Pages / 595.276 x 790.866 pts Page_size
- 81 Downloads / 212 Views
ORIGINAL PAPER
Identification of saquinavir as a potent inhibitor of dimeric SARS-CoV2 main protease through MM/GBSA Martiniano Bello 1
&
Alberto Martínez-Muñoz 1 & Irving Balbuena-Rebolledo 1
Received: 18 June 2020 / Accepted: 5 November 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Among targets selected for studies aimed at identifying potential inhibitors against COVID-19, SARS-CoV2 main proteinase (Mpro) is highlighted. Mpro is indispensable for virus replication and is a promising target of potential inhibitors of COVID-19. Recently, monomeric SARS-CoV2 Mpro, drug repurposing, and docking methods have facilitated the identification of several potential inhibitors. Results were refined through the assessment of dimeric SARS-CoV2 Mpro, which represents the functional state of enzyme. Docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area (MM/GBSA) studies indicated that dimeric Mpro most significantly impacts binding affinity tendency compared with the monomeric state, which suggests that dimeric state is most useful when performing studies aimed at identifying drugs targeting Mpro. In this study, we extend previous research by performing docking and MD simulation studies coupled with an MM/GBSA approach to assess binding of dimeric SARS-CoV2 Mpro to 12 FDA-approved drugs (darunavir, indinavir, saquinavir, tipranavir, diosmin, hesperidin, rutin, raltegravir, velpatasvir, ledipasvir, rosuvastatin, and bortezomib), which were identified as the best candidates for the treatment of COVID-19 in some previous dockings studies involving monomeric SARSCoV2 Mpro. This analysis identified saquinavir as a potent inhibitor of dimeric SARS-CoV2 Mpro; therefore, the compound may have clinical utility against COVID-19. Keywords Protease . SARS-CoV2 . Docking . MD simulations
Introduction The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) was first reported on December 30, 2019, in Wuhan China [1]. SARS-CoV2 belongs to the beta coronavirus group and is similar to SARS-coronaviruses. Despite sequence diversity, its spike protein binds strongly to the human ACE2 receptor [1]. The disease caused by SARS-CoV2 was named coronavirus disease 2019 (COVID-19) by World Health Organization and represents a grave menace to global public health and local economies. As of May 2, 2020, over 3,362,778 cases of COVID-19 have been reported in 187 countries and have caused 239,227 total
* Martiniano Bello [email protected]; [email protected] 1
Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México, Plan de San Luis Y Diaz Mirón S/N, Col. Casco de Santo Tomas, 11340 México City, Mexico
deaths (https://coronavirus.jhu.edu/map.html). Therefore, we must urgently identify effective, available, and affordable drugs to treat COVID-19 to reduce the toll of the epidemic. A potential treatment for COVID-19 involves combining two HIV-1 proteas
Data Loading...
