Identifying Drug Candidates for COVID-19 with Large-Scale Drug Screening

Papain-like protease (PLpro) is critical to COVID-19 infection. Therefore, it is a significant target protein for drug development. We virtually screened a 26,193 compound library against the PLpro of SARS-CoV-2 and identified several drug candidates with convincing binding affinities. The three best compounds all had better estimated binding energy than those of the drug candidates proposed in previous studies. By analyzing the docking results for the drug candidates identified in this and previous studies, we demonstrate that the critical interactions between the compounds and PLpro proposed by the computational approaches are consistent with those proposed by the biological experiments. In addition, the predicted binding energies of the compounds in the dataset showed a similar trend as their IC50 values. The predicted ADME and drug-likeness properties also suggested that these identified compounds can be used for COVID-19 treatment.

[1]  D. Komander,et al.  Inhibitors of SARS-CoV-2 PLpro , 2022, Frontiers in Chemistry.

[2]  Mohammed Al-Kassim Hassan,et al.  Delayed Access to COVID-19 Vaccines: A Perspective on Low-income Countries in Africa , 2022, International journal of health services : planning, administration, evaluation.

[3]  S. Olsen,et al.  Targeting SARS-CoV-2 Proteases for COVID-19 Antiviral Development , 2022, Frontiers in Chemistry.

[4]  Seungtaek Kim.  COVID-19 Drug Development , 2021, Journal of microbiology and biotechnology.

[5]  G. Thatcher,et al.  Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity , 2021, Journal of medicinal chemistry.

[6]  Kuan Y. Chang,et al.  Polyphenols as alternative treatments of COVID-19 , 2021, Computational and Structural Biotechnology Journal.

[7]  Fatimawali,et al.  Data on the docking of phytoconstituents of betel plant and matcha green tea on SARS-CoV-2 , 2021, Data in Brief.

[8]  Jakub M. Tomczak,et al.  Identification of ebselen and its analogues as potent covalent inhibitors of papain-like protease from SARS-CoV-2 , 2021, Scientific Reports.

[9]  Taufiq Rahman,et al.  Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease , 2021, Molecules.

[10]  Jiayun Zhang,et al.  RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic , 2021, European Journal of Medicinal Chemistry.

[11]  M. Sturlese,et al.  Supervised Molecular Dynamics (SuMD) Insights into the mechanism of action of SARS-CoV-2 main protease inhibitor PF-07321332 , 2021, Journal of Enzyme Inhibition and Medicinal Chemistry.

[12]  M. Ahamed,et al.  Virtual screening of phytoconstituents from miracle herb nigella sativa targeting nucleocapsid protein and papain-like protease of SARS-CoV-2 for COVID-19 treatment , 2020, Journal of biomolecular structure & dynamics.

[13]  R. Urman,et al.  Economic impact of COVID-19 pandemic on healthcare facilities and systems: International perspectives , 2020, Best Practice & Research Clinical Anaesthesiology.

[14]  Peter V. Coveney,et al.  Rapid, accurate, precise and reproducible ligand–protein binding free energy prediction , 2020, Interface Focus.

[15]  A. Roy,et al.  Cyanobacterial metabolites as promising drug leads against the Mpro and PLpro of SARS-CoV-2: an in silico analysis , 2020, Journal of biomolecular structure & dynamics.

[16]  Yiliang Wang,et al.  Progress in the Research and Development of Anti-COVID-19 Drugs , 2020, Frontiers in Public Health.

[17]  Kayhan Ozkan,et al.  How Close are We to a COVID-19 Vaccine? , 2020, Journal of Pure and Applied Microbiology.

[18]  E. Holmes,et al.  A new coronavirus associated with human respiratory disease in China , 2020, Nature.

[19]  Chunlong Ma,et al.  Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease , 2020, Cell Research.

[20]  Robert Abel,et al.  OPLS3e: Extending Force Field Coverage for Drug-Like Small Molecules. , 2019, Journal of chemical theory and computation.

[21]  Rolf Hilgenfeld,et al.  Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein , 2017, Antiviral Research.

[22]  Alexander D. MacKerell,et al.  CHARMM36: An Improved Force Field for Folded and Intrinsically Disordered Proteins , 2017 .

[23]  Arun K. Ghosh,et al.  Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ from That of SARS-CoV , 2015, ACS chemical biology.

[24]  Thomas Sander,et al.  DataWarrior: An Open-Source Program For Chemistry Aware Data Visualization And Analysis , 2015, J. Chem. Inf. Model..

[25]  Woody Sherman,et al.  Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments , 2013, Journal of Computer-Aided Molecular Design.

[26]  Katrina Sleeman,et al.  Structure-based design, synthesis, and biological evaluation of a series of novel and reversible inhibitors for the severe acute respiratory syndrome-coronavirus papain-like protease. , 2009, Journal of medicinal chemistry.

[27]  Alexander D. MacKerell,et al.  CHARMM general force field: A force field for drug‐like molecules compatible with the CHARMM all‐atom additive biological force fields , 2009, J. Comput. Chem..

[28]  Taehoon Kim,et al.  CHARMM‐GUI: A web‐based graphical user interface for CHARMM , 2008, J. Comput. Chem..

[29]  Jeremy R. Greenwood,et al.  Epik: a software program for pKa prediction and protonation state generation for drug-like molecules , 2007, J. Comput. Aided Mol. Des..

[30]  Jan H. Jensen,et al.  Very fast empirical prediction and rationalization of protein pKa values , 2005, Proteins.

[31]  W. L. Jorgensen.  The Many Roles of Computation in Drug Discovery , 2004, Science.

[32]  Niall Johnson,et al.  Updating the Accounts: Global Mortality of the 1918-1920 "Spanish" Influenza Pandemic , 2002, Bulletin of the history of medicine.

[33]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings , 1997 .

[34]  D. Mant.  Prevention , 1994, The Lancet.

[35]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..