Discovery of small molecule PLpro inhibitor against COVID-19 using structure-based virtual screening, molecular dynamics
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ORIGINAL RESEARCH
Discovery of small molecule PLpro inhibitor against COVID-19 using structure-based virtual screening, molecular dynamics simulation, and molecular mechanics/Generalized Born surface area (MM/GBSA) calculation Jie Pang 1 & Shan Gao 1 & Zengxian Sun 1 & Guangsheng Yang 1 Received: 17 August 2020 / Accepted: 15 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract COVID-19 is spreading in a global pandemic that is endangering human life and health. Therefore, there is an urgent need to target COVID-19 to find effective treatments for this emerging acute respiratory infection. Viral Papain-Like cysteine protease (PLpro), similar to papain and the cysteine deubiquitinase enzyme, has been a popular target for coronavirus inhibitors, as an indispensable enzyme in the process of coronavirus replication and infection of the host. Combined structure-based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics/Generalized Born surface area (MM/GBSA) free energy calculation approaches were utilized for identification of PLpro inhibitors. Four compounds (F403_0159, F112_0109, G805_0497, D754_0006) with diverse chemical scaffolds were retrieved as hits based on docking score and clustering analysis. Molecular dynamics simulations indicated that the contribution of van der Waals interaction dominated the binding free energies of these compounds, which may be attributed to the hydrophobicity of active site of PLpro from COVID-19. Moreover, all four compounds formed conservative hydrogen bonds with the residues Asp164, Gln269, and Tyr273. We hoped that these four compounds might represent the promising chemical scaffolds for further development of novel PLpro inhibitors against COVID-19. Keywords COVID-19 . PLpro inhibitor . Virtual screening . Molecular dynamics simulation
Introduction Since December 31, 2019, when the Chinese Center for Disease Control (China CDC) reported a cluster of severe pneumonia in the city of Wuhan in the Hubei Province, tens of millions of cases had been confirmed globally. It was found that the pathogen was a novel coronavirus previously unknown in humans, namely novel coronavirus 2019. On February 11, 2020, the World Health Organization (WHO) named it Corona Virus Disease 2019 (COVID-19) [1]. In light Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11224-020-01665-y) contains supplementary material, which is available to authorized users. * Guangsheng Yang [email protected] 1
Xuzhou Medical University Affiliated of Lianyungang Hospital, Lianyungang, Jiangsu, People’s Republic of China
of the highly homologous between COVID-19 and severe acute respiratory syndrome (SARS), the International Virus Classification Commission (ICTV) classified the COVID-19 viruses as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [2, 3]. Common symptoms of COVID-19 infection included respiratory symptoms, fever, cough, and dyspnea. In more severe cases, the infection could lead t
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