Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL pro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates

We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL pro) using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart. With the 3CL pro molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache. The drugs Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.

[1]  M. Hsu,et al.  Mechanism of the Maturation Process of SARS-CoV 3CL Protease , 2005, Journal of Biological Chemistry.

[2]  S. Lo,et al.  A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster , 2020, The Lancet.

[3]  S. Jockusch,et al.  Nucleotide Analogues as Inhibitors of Viral Polymerases , 2020, bioRxiv.

[4]  Martin J. Stoermer,et al.  Homology Models of Wuhan Coronavirus 3CLpro Protease , 2020 .

[5]  Xiu-Jie Wang,et al.  Potential inhibitors for 2019-nCoV coronavirus M protease from clinically approved medicines , 2020, bioRxiv.

[6]  Paul Garner,et al.  SARS: Systematic Review of Treatment Effects , 2006, PLoS medicine.

[7]  B. Beck,et al.  Predicting commercially available antiviral drugs that may act on the novel coronavirus (2019-nCoV), Wuhan, China through a drug-target interaction deep learning model , 2020, bioRxiv.

[8]  Zihe Rao,et al.  Structure of Mpro from COVID-19 virus and discovery of its inhibitors , 2020, medRxiv.

[9]  Pierre Tufféry,et al.  MTiOpenScreen: a web server for structure-based virtual screening , 2015, Nucleic Acids Res..

[10]  S. Lindstrom,et al.  First Case of 2019 Novel Coronavirus in the United States , 2020, The New England journal of medicine.

[11]  J. Richardson,et al.  The penultimate rotamer library , 2000, Proteins.

[12]  Xiu-Jie Wang,et al.  Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines , 2020, Journal of Genetics and Genomics.

[13]  Yuan Wei,et al.  A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19 , 2020, The New England journal of medicine.

[14]  S. Yokoyama,et al.  SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity , 2016, Proceedings of the National Academy of Sciences.

[15]  M. Dayer,et al.  Lopinavir; A Potent Drug against Coronavirus Infection: Insight from Molecular Docking Study , 2017 .

[16]  V. Lee,et al.  Molecular dynamic simulations analysis of ritronavir and lopinavir as SARS-CoV 3CLpro inhibitors , 2008, Journal of Theoretical Biology.

[17]  L. Amzel,et al.  Mutation of Asn28 disrupts the dimerization and enzymatic activity of SARS 3CL(pro) . , 2010, Biochemistry.

[18]  Hsuan-Cheng Huang,et al.  Small molecules targeting severe acute respiratory syndrome human coronavirus. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Jian Zhang,et al.  Residues on the Dimer Interface of SARS Coronavirus 3C-like Protease: Dimer Stability Characterization and Enzyme Catalytic Activity Analysis , 2007, Journal of biochemistry.

[20]  G. Chang,et al.  Mutation of Glu-166 Blocks the Substrate-Induced Dimerization of SARS Coronavirus Main Protease , 2010, Biophysical Journal.

[21]  Bonggun Shin,et al.  Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model , 2020, Computational and Structural Biotechnology Journal.

[22]  Hualiang Jiang,et al.  Two adjacent mutations on the dimer interface of SARS coronavirus 3C-like protease cause different conformational changes in crystal structure☆ , 2009, Virology.

[23]  Y. Hayashi,et al.  An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy , 2016, Journal of medicinal chemistry.

[24]  Weiliang Zhu,et al.  Nelfinavir was predicted to be a potential inhibitor of 2019-nCov main protease by an integrative approach combining homology modelling, molecular docking and binding free energy calculation , 2020, bioRxiv.

[25]  Y. Guan,et al.  Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings , 2004, Thorax.

[26]  Yan Li,et al.  Therapeutic Drugs Targeting 2019-nCoV Main Protease by High-Throughput Screening , 2020, bioRxiv.

[27]  Julie Dyall,et al.  Repurposing of Clinically Developed Drugs for Treatment of Middle East Respiratory Syndrome Coronavirus Infection , 2014, Antimicrobial Agents and Chemotherapy.

[28]  Guo-Wei Wei,et al.  Machine intelligence design of 2019-nCoV drugs , 2020, bioRxiv.

[29]  Y. Liu,et al.  3C-like proteinase from SARS coronavirus catalyzes substrate hydrolysis by a general base mechanism. , 2004, Biochemistry.

[30]  Y. Yap,et al.  Old drugs as lead compounds for a new disease? Binding analysis of SARS coronavirus main proteinase with HIV, psychotic and parasite drugs , 2004, Bioorganic & Medicinal Chemistry.

[31]  E. Freire,et al.  Long-range cooperative interactions modulate dimerization in SARS 3CLpro. , 2006, Biochemistry.

[32]  F. Tsai,et al.  Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds , 2005, Antiviral Research.

[33]  P. Liang,et al.  Characterization and Inhibition of the Main Protease of Severe Acute Respiratory Syndrome Coronavirus , 2015, ChemBioEng Reviews.

[34]  Roland L. Dunbrack,et al.  proteins STRUCTURE O FUNCTION O BIOINFORMATICS Improved prediction of protein side-chain conformations with SCWRL4 , 2022 .

[35]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[36]  R. Hilgenfeld,et al.  Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors , 2020, Science.