We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL ) 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 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. How to cite this article:Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL ) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates [version 1; peer review: 2 F1000Research 2020, :129 ( ) approved] 9 https://doi.PubMed Abstract | Publisher Full Text 2. Muramatsu T, Takemoto C, Kim YT, et al.: SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity. Proc Natl Acad Sci U S A. 2016; 113(46): 12997-13002. PubMed Abstract | Publisher Full Text | Free Full Text 3. Krivov GG, Shapovalov MV, Dunbrack RL Jr: Improved prediction of protein side-chain conformations with SCWRL4. Proteins. 2009; 77(4): 778-795. PubMed Abstract | Publisher Full Text | Free Full Text 4. Labbé CM, Rey J, Lagorce D, et al.: MTiOpenScreen: a web server for structure-based virtual screening. Nucleic Acids Res. 2015; 43(W1): W448-W454. PubMed Abstract | Publisher Full Text | Free Full Text 5. Trott O, Olson AJ: AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010; 31(2): 455-461. PubMed Abstract | Publisher Full Text | Free Full Text The PyMOL molecular graphics system (Schrödinger, LLC). Reference Source 7. Chen YW: SARS-CoV-2 (2019-nCoV) 3CLpro Model & Screening. 2020. http://www.doi.org/10.17605/OSF.IO/HCU8X 8. Huang C, Wei P, Fan K, et al.: 3C-like proteinase from SARS coronavirus catalyzes substrate hydrolysis by a general base mechanism. Biochemistry. 2004; 43(15): 4568-4574. PubMed Abstract | Publisher Full Text 9. Hsu MF, Kuo CJ, Chang KT, et al.: Mechanism of the maturation process of SARS-CoV 3CL protease. J Biol Chem. 2005; 280(35): 31257-31266. PubMed Abstract | Publisher Full Text 10. Barrila J, Bacha U, Freire E: Long-range cooperative interactions modulate dimerization in SARS 3CL pro . Biochemistry. 2006...

We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL ) 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 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. pro 1. Chan JF, Yuan S, Kok KH, et al.: A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020; 395(10223): 514-523.PubMed Abstract | Publisher Full Text 2. Muramatsu T, Takemoto C, Kim YT, et al.: SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity. Proc Natl Acad Sci U S A. 2016; 113(46): 12997-13002. PubMed Abstract | Publisher Full Text | Free Full Text 3. Krivov GG, Shapovalov MV, Dunbrack RL Jr: Improved prediction of protein sidechain conformations with SCWRL4. Proteins. 2009; 77(4): 778-795. PubMed Abstract | Publisher Full Text | Free Full Text 4. Labbé CM, Rey J, Lagorce D, et al.: MTiOpenScreen: a web server for structurebased virtual screening. Nucleic Acids Res. 2015; 43(W1): W448-W454. PubMed Abstract | Publisher Full Text | Free Full Text 5. Trott O, Olson AJ: AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010; 31(2): 455-461. PubMed Abstract | Publisher Full Text | Free Full Text 6. Huang C, Wei P, Fan K, et al.: 3C-like proteinase from SARS coronavirus catalyzes substrate hydrolysis by a general base mechanism. Biochemistry. 2004; 43(15): 4568-4574. PubMed Abstract | Publisher Full Text 7. Hsu MF, Kuo CJ, Chang KT, et al.: Mechanism of the maturation process of SARS-CoV 3CL protease. J Biol Chem. 2005; 280(35): 31257-31266. PubMed Abstract | Publisher Full Text 8. Barrila J, Bacha U, Freire E: Long-range cooperative interactions modulate dimerization in SARS 3CL pro . Biochemistry. 2006; 45(50): 14908-14916. PubMed Abstract | Publisher Full Text | Free Full Text 9. Barrila J, Gabelli SB, Bacha U, et al.: Mutation of Asn28 disrupts the dimerization and enzymatic activity of SARS 3CL pro . Biochemistry. 2010; 49(20): ...

<p>We prepared the three-dimensional model of the 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 in the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its 2019-nCoV 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 2019-nCoV 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.</p>

We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL ) 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 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. How to cite this article:Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL ) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates [version 2; peer review: 3 F1000Research 2020, :129 ( ) approved] 9 https://doi.pro 1. Chan JF, Yuan S, Kok KH, et al.: A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020; 395(10223): 514-523. PubMed Abstract | Publisher Full Text 2. Muramatsu T, Takemoto C, Kim YT, et al.: SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity. Proc Natl Acad Sci U S A. 2016; 113(46): 12997-13002. PubMed Abstract | Publisher Full Text | Free Full Text 3. Krivov GG, Shapovalov MV, Dunbrack RL Jr: Improved prediction of protein sidechain conformations with SCWRL4. Proteins. 2009; 77(4): 778-795. PubMed Abstract | Publisher Full Text | Free Full Text 4. Labbé CM, Rey J, Lagorce D, et al.: MTiOpenScreen: a web server for structurebased virtual screening. Nucleic Acids Res. 2015; 43(W1): W448-W454. PubMed Abstract | Publisher Full Text | Free Full Text 5. Trott O, Olson AJ: AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010; 31(2): 455-461. PubMed Abstract | Publisher Full Text | Free Full Text 6. Huang C, Wei P, Fan K, et al.: 3C-like proteinase from SARS coronavirus catalyzes substrate hydrolysis by a general base mechanism. Biochemistry. 2004; 43(15): 4568-4574. PubMed Abstract | Publisher Full Text 7. Hsu MF, Kuo CJ, Chang KT, et al.: Mechanism of the maturation process of SARS-CoV 3CL protease. J Biol Chem. 2005; 280(35): 31257-31266. PubMed Abstract | Publisher Full Text 8. Barrila J, Bacha U, Freire E: Long-range cooperative interactions modulate dimerization...

<p>We prepared the three-dimensional model of the 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 in the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its 2019-nCoV 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 2019-nCoV 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.</p>