1,2,4 triazolo[1,5-a] pyrimidin-7-ones as novel SARS-CoV-2 Main protease inhibitors: In silico screening and molecular dynamics simulation of potential COVID-19 drug candidates

Kuppuswamy Kavitha

Subramaniam Sivakumar

Balasubramanian Ramesh

^{Research Department of Microbiology, Sri Sankara Arts and Science College, Kanchipuram 631 561, India}

^{Research Department of Biochemistry, Sri Sankara Arts and Science College, Kanchipuram 631 561, India}

^{Research Department of Biotechnology, Sri Sankara Arts and Science College, Kanchipuram 631 561, India}

^{Corresponding author at: Research Department of Biotechnology, Sri Sankara Arts and Science College, Enathur, Kanchipuram 631 561, India.}

Received 2020 Jul 9; Revised 2020 Sep 6; Accepted 2020 Sep 14.

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Discovery of a potent SARS-CoV-2 main protease (M^{) inhibitor is the need of the hour to combat COVID-19. A total of 1000 protease-inhibitor-like compounds available in the ZINC database were screened by molecular docking with SARS-CoV-2 M}^{and the top 2 lead compounds based on binding affinity were found to be 1,2,4 triazolo[1,5-a] pyrimidin-7-one compounds. We report these two compounds (ZINC000621278586 and ZINC000621285995) as potent SARS-CoV-2 M}^{inhibitors with high affinity (<−9 kCal/mol) and less toxicity than Lopinavir and Nelfinavir positive controls. Both the lead compounds effectively interacted with the crucial active site amino acid residues His41, Cys145 and Glu166. The lead compounds satisfied all of the druglikeness rules and devoid of toxicity or mutagenicity. Molecular dynamics simulations showed that both lead 1 and lead 2 formed stable complexes with SARS-CoV-2 M}^{as evidenced by the highly stable root mean square deviation (<0.23 nm), root mean square fluctuations (0.12 nm) and radius of gyration (2.2 nm) values. Molecular mechanics Poisson-Boltzmann surface area calculation revealed thermodynamically stable binding energies of −129.266 ± 2.428 kJ/mol and − 116.478 ± 3.502 kJ/mol for lead1 and lead2 with SARS-CoV-2 M}^{, respectively.}A) Evolutionary relationships of SARS-CoV-2 M^{sequences extracted from PDB structures 6 LU7, 6Y84, 6YB7, 6 W63, 5RE4 and SARS-CoV main protease structures 5NHO, 1P95 and 2ZU2 inferred using the neighbor-joining method. The evolutionary distances are in units of the number of amino acid substitutions per site. B) Structure-based sequence alignment of SARS-CoV-2 and SARS-CoV main proteases is shown and their secondary structural features are shown above and below the alignment, respectively. Amino acids conserved in all sequences are shaded. Active site amino acid dyad His41 and Cys145 are labeled in red and blue, respectively. The dimerization site amino acid Glu166 is well conserved in all SARS-CoV-2 M}^{and SARS-CoVM}^{sequences. All other active site aminoacids of SARS-CoV-2 M}^{are labeled in black.}Crystal structure of SARS-CoV-2 M^{enzyme. A) X-ray crystallographic structure of SARS-CoV-2 M}^{shown as cartoon representation. Domains I, II and III are shown in green, orange and blue, respectively and labeled at the top. N-finger is shown in Magenta. B) Druggable binding pocket predicted by CASTp 3.0 with a solvent-accessible area of 351.125 Å}^{and volume of 319.370 Å}^{. The active site dyad His41 (Red) and Cys145 (Blue) are labeled. Glu166, which is essential for the dimerization of M}^{, is labeled and shown in Cyan.}

Top 10 Lead compounds with positive controls based on docking results.

The lead compounds were ranked on the basis of AutoDock Vina Binding Affinity between the lead compound and SARS-CoV2 M^{(Least energy the better binding).}The binding affinity of Lead-1 i.e. -9.3 is in bold to highlight least value. His41, Cys145 and Glu166 are in bold to show their importance in the active site of SARS-CoV2 M^.Molecular docking of SARS-CoV-2 M^{with Lead compounds. (A) The binding of Lead1 is in the groove between Domain-I and Domain-II chymotrypsin-like β barrel, where the active site is located and binds exactly with active site dyads His41 (Red), Cys145 (Blue) and Mpro dimerization amino acid Glu166 (Cyan). (B) Binding of Lead 2 with SARS-CoV-2 M}^{at the same active site.}

ADME/Tox properties of lead compounds and positive controls.

#Cytochrome P450 Inhibitors include inhibitors of CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4; all the molecules showed a bioavailability score of 0.55; ^{Pan assay interference compounds alert;}^{105 fragments identified by Brenk database;}^{Synthetic accessibility score on a scale of 1–10 (1 easy to 10 difficult to synthesize).}A) Root-Mean-Square Deviation (RMSD) of the unliganded SARS-CoV-2-M^{(Black), SARS-CoV-2-M}^{-Lead1 complex (Red) and SARS-CoV-2-M}^{-Lead2 complex (Magenta), SARS-CoV-2-M}^{-Lead3 complex (Blue), SARS-CoV-2-M}^{-Lopinavir complex (Green) and SARS-CoV-2-M}^{-Nelfinavir complex (Cyan) in nm plotted against time (ps). B) Radius of gyration (Rg) of unliganded SARS-CoV-2-M}^{(Black), SARS-CoV-2-M}^{-Lead1 complex (Red) and SARS-CoV-2-M}^{-Lead2 complex (Magenta), SARS-CoV-2-M}^{-Lead3 complex (Blue), SARS-CoV-2-M}^{-Lopinavir complex (Green) and SARS-CoV-2-M}^{-Nelfinavir complex (Cyan) in nm plotted against time (ps).}Root-Mean-Square Fluctuation (RMSF) of unliganded SARS-CoV-2-M^{(Black), SARS-CoV-2-M}^{-Lead1 complex (Red) and SARS-CoV-2-M}^{-Lead2 complex (Magenta), SARS-CoV-2-M}^{-Lead3 complex (Blue), SARS-CoV-2-M}^{-Lopinavir complex (Green) and SARS-CoV-2-M}^{-Nelfinavir complex (Cyan) in nm plotted against the number of amino acid residues.}Number of hydrogen bond interactions during simulation between protein and ligand complexes of SARS-CoV-2-M^{-Lead1 complex (Red) and SARS-CoV-2-M}^{-Lead2 complex (Magenta), SARS-CoV-2-M}^{-Lead3 complex (Blue), SARS-CoV-2-M}^{-Lopinavir complex (Green) and SARS-CoV-2-M}^{-Nelfinavir complex (Cyan) plotted against time (ps).}Thermodynamic parameters for complexes of lead compounds and positive controls with SARS-CoV-2-M^.Energy contribution by the binding of ligands during simulation between protein and ligand complexes of SARS-CoV-2-M^{-Lead1 complex (Red), SARS-CoV-2-M}^{-Lead2 complex (Magenta) and SARS-CoV-2-M}^{-Lead3 complex (Blue) SARS-CoV-2-M}^{-Lopinavir complex (Green) and SARS-CoV-2-M}^{-Nelfinavir complex (Cyan) plotted against amino acid residues. Negative values indicate a stabilization effect for SARS-CoV-2-M}^{-ligand interactions, whereas positive values indicate a destabilization effect for SARS-CoV-2-M}^{-ligand interactions.}

Declaration of Competing Interest

The authors declare that they have no conflicts of interest.

Declaration of Competing Interest

Footnotes

^{Supplementary data to this article can be found online at}https://doi.org/10.1016/j.bpc.2020.106478.

Footnotes

Pharmacokinetics, Bioavailability, Druglikeness, Medicinal Chemistry, Toxicity, carcinogenesis and Physicochemical Properties of all 10 Lead compounds and positive controls

Click here to view.^{Image 13}

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