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      Repurposing clinically approved drugs for COVID-19 treatment targeting SARS-CoV-2 papain-like protease

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          Abstract

          COVID-19 is a disease caused by SARS-CoV-2, which has led to more than 4 million deaths worldwide. As a result, there is a worldwide effort to develop specific drugs for targeting COVID-19. Papain-like protease (PLpro) is an attractive drug target because it has multiple essential functions involved in processing viral proteins, including viral genome replication and removal of post-translational ubiquitination modifications. Here, we established two assays for screening PLpro inhibitors according to protease and anti-ISGylation activities, respectively. Application of the two screening techniques to the library of clinically approved drugs led to the discovery of tanshinone IIA sulfonate sodium and chloroxine with their IC50 values of lower than 10 μM. These two compounds were found to directly interact with PLpro and their molecular mechanisms of binding were illustrated by docking and molecular dynamics simulations. The results highlight the usefulness of the two developed screening techniques for locating PLpro inhibitors.

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          AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.

          Oleg Trott, Arthur Olson (2010)
          AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user. Copyright 2009 Wiley Periodicals, Inc.
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            Development and testing of a general amber force field.

            Junmei Wang, Romain M. Wolf, James W. Caldwell … (2004)
            We describe here a general Amber force field (GAFF) for organic molecules. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most organic and pharmaceutical molecules that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited number of atom types, but incorporates both empirical and heuristic models to estimate force constants and partial atomic charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallographic structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 A, which is comparable to that of the Tripos 5.2 force field (0.25 A) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 A, respectively). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermolecular energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 A and 1.2 kcal/mol, respectively. These data are comparable to results from Parm99/RESP (0.16 A and 1.18 kcal/mol, respectively), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to experiment) is about 0.5 kcal/mol. GAFF can be applied to wide range of molecules in an automatic fashion, making it suitable for rational drug design and database searching. Copyright 2004 Wiley Periodicals, Inc.
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              GROMACS: fast, flexible, and free.

              David van der Spoel, Erik Lindahl, Berk Hess … (2005)
              This article describes the software suite GROMACS (Groningen MAchine for Chemical Simulation) that was developed at the University of Groningen, The Netherlands, in the early 1990s. The software, written in ANSI C, originates from a parallel hardware project, and is well suited for parallelization on processor clusters. By careful optimization of neighbor searching and of inner loop performance, GROMACS is a very fast program for molecular dynamics simulation. It does not have a force field of its own, but is compatible with GROMOS, OPLS, AMBER, and ENCAD force fields. In addition, it can handle polarizable shell models and flexible constraints. The program is versatile, as force routines can be added by the user, tabulated functions can be specified, and analyses can be easily customized. Nonequilibrium dynamics and free energy determinations are incorporated. Interfaces with popular quantum-chemical packages (MOPAC, GAMES-UK, GAUSSIAN) are provided to perform mixed MM/QM simulations. The package includes about 100 utility and analysis programs. GROMACS is in the public domain and distributed (with source code and documentation) under the GNU General Public License. It is maintained by a group of developers from the Universities of Groningen, Uppsala, and Stockholm, and the Max Planck Institute for Polymer Research in Mainz. Its Web site is http://www.gromacs.org. (c) 2005 Wiley Periodicals, Inc.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Biol Macromol
                Journal ID (iso-abbrev): Int J Biol Macromol
                Title: International Journal of Biological Macromolecules
                Publisher: Elsevier B.V.
                ISSN (Print): 0141-8130
                ISSN (Electronic): 1879-0003
                Publication date PMC-release: 6 August 2021
                Publication date (Print): 1 October 2021
                Publication date (Electronic): 6 August 2021
                Volume: 188
                Pages: 137-146
                Affiliations
                [a ]Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China
                [b ]Shenzhen Graduate School, Peking University, Shenzhen, Guangdong 518055, China
                [c ]Institute for Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518038, China
                [d ]Institute for Glycomics, Griffith University, Southport, Queensland 4222, Australia
                [e ]Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China
                [f ]Department of Developmental Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong 510515, China
                [g ]Biosafety Level-3 Laboratory, School of Public Health, Southern Medical University, Guangzhou 510515, China.
                Author notes
                [* ]Correspondence to: Y. Zhou, Shenzhen Graduate School, Peking University, Shenzhen, Guangdong 518055, China.
                [** ]Correspondence to: J. Zhan, Institute for Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518038, China
                [*** ]Correspondence to: W. Xu, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China.
                [1]

                These authors contributed equally.

                Article
                Publisher Item ID: S0141-8130(21)01644-5
                DOI: 10.1016/j.ijbiomac.2021.07.184
                PMC ID: 8342870
                PubMed ID: 34364941
                SO-VID: 283136cf-8193-4452-bcaf-98664ca96d3f
                Copyright © © 2021 Elsevier B.V. All rights reserved.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 3 April 2021
                Date revision received : 5 July 2021
                Date accepted : 28 July 2021
                Categories
                Subject: Article

                ScienceOpen disciplines: Biochemistry
                Keywords: papain-like protease,tanshinone iia sulfonate sodium,chloroxine
                Data availability:
                ScienceOpen disciplines: Biochemistry
                Keywords: papain-like protease, tanshinone iia sulfonate sodium, chloroxine

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