Quantum Biochemistry and MM-PBSA Description of the ZIKV NS2B-NS3 Protease: Insights into the Binding Interactions beyond the Catalytic Triad Pocket.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Zika Virus*/metabolism ; Zika Virus Infection*; Molecular Dynamics Simulation ; Peptide Hydrolases/metabolism ; Protease Inhibitors/chemistry ; Serine Endopeptidases/metabolism ; Succinates ; Viral Nonstructural Proteins/metabolism

The Zika virus protease NS2B-NS3 has a binding site formed with the participation of a H51-D75-S135 triad presenting two forms, active and inactive. Studies suggest that the inactive conformation is a good target for the design of inhibitors. In this paper, we evaluated the co-crystallized structures of the protease with the inhibitors benzoic acid (5YOD) and benzimidazole-1-ylmethanol (5H4I). We applied a protocol consisting of two steps: first, classical molecular mechanics energy minimization followed by classical molecular dynamics were performed, obtaining stabilized molecular geometries; second, the optimized/relaxed geometries were used in quantum biochemistry and molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) calculations to estimate the ligand interactions with each amino acid residue of the binding pocket. We show that the quantum-level results identified essential residues for the stabilization of the 5YOD and 5H4I complexes after classical energy minimization, matching previously published experimental data. The same success, however, was not observed for the MM-PBSA simulations. The application of quantum biochemistry methods seems to be more promising for the design of novel inhibitors acting on NS2B-NS3.

Curr Opin Virol. 2019 Apr;35:19-26. (PMID: 30852345)
N Engl J Med. 2009 Jun 11;360(24):2536-43. (PMID: 19516034)
Structure. 2018 Apr 3;26(4):555-564.e3. (PMID: 29526431)
Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11578-83. (PMID: 9751708)
Phys Chem Chem Phys. 2020 Feb 14;22(6):3570-3583. (PMID: 31995079)
Phys Chem Chem Phys. 2018 Sep 12;20(35):22818-22830. (PMID: 30151512)
Protein Sci. 2009 May;18(5):1003-11. (PMID: 19388022)
Phys Chem Chem Phys. 2014 Oct 28;16(40):22035-45. (PMID: 25205360)
J Cheminform. 2012 Aug 13;4(1):17. (PMID: 22889332)
Structure. 2017 Aug 1;25(8):1242-1250.e3. (PMID: 28689970)
J Chem Phys. 2007 Jan 7;126(1):014101. (PMID: 17212484)
J Phys Chem B. 2013 Jul 18;117(28):8408-21. (PMID: 23789789)
N Engl J Med. 2016 Mar 10;374(10):951-8. (PMID: 26862926)
J Phys Chem A. 2013 Aug 15;117(32):7149-61. (PMID: 23452268)
Bioorg Med Chem. 2016 Oct 15;24(20):4812-4825. (PMID: 27353885)
PLoS One. 2012;7(10):e46902. (PMID: 23077531)
Molecules. 2019 Nov 12;24(22):. (PMID: 31726716)
Chem Rev. 2018 Apr 25;118(8):4448-4482. (PMID: 29652486)
J Mol Graph Model. 2015 Nov;62:303-318. (PMID: 26550792)
Curr Opin Virol. 2012 Apr;2(2):168-75. (PMID: 22445964)
Viruses. 2015 Aug 13;7(8):4640-56. (PMID: 26287232)
Bioinformatics. 2013 Apr 1;29(7):845-54. (PMID: 23407358)
Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W665-7. (PMID: 15215472)
Antiviral Res. 2013 May;98(2):192-208. (PMID: 23523765)
Biochem Biophys Res Commun. 2017 Oct 28;492(4):643-651. (PMID: 28341122)
Curr Protoc Bioinformatics. 2008 Dec;Chapter 8:Unit 8.14. (PMID: 19085980)
Biochem Pharmacol. 2018 Aug;154:54-63. (PMID: 29674002)
Electrophoresis. 2009 Jun;30 Suppl 1:S162-73. (PMID: 19517507)
Virus Res. 2018 Aug 15;255:133-140. (PMID: 30031046)
Emerg Microbes Infect. 2017 Mar 22;6(3):e13. (PMID: 28325921)
J Chem Inf Model. 2020 Feb 24;60(2):1005-1018. (PMID: 31880447)
Cell Microbiol. 2018 Aug;20(8):e12884. (PMID: 29933527)
Expert Opin Drug Discov. 2015 May;10(5):449-61. (PMID: 25835573)
Phys Chem Chem Phys. 2018 May 30;20(21):14450-14460. (PMID: 29785435)
J Virol. 2013 Apr;87(8):4609-22. (PMID: 23408612)
J Chem Theory Comput. 2008 Jan;4(1):116-22. (PMID: 26619985)
J Med Chem. 2012 Jul 26;55(14):6278-93. (PMID: 22742496)
Biochim Biophys Acta. 2015 Oct;1848(10 Pt A):2244-52. (PMID: 26072288)
Proteins. 2020 Feb;88(2):345-354. (PMID: 31461176)
Eur J Med Chem. 2012 Dec;58:431-40. (PMID: 23153814)
J Comput Aided Mol Des. 2012 May;26(5):527-41. (PMID: 22198518)
Protein J. 2014 Feb;33(1):32-47. (PMID: 24374429)
Phys Rev Lett. 2009 Feb 20;102(7):073005. (PMID: 19257665)
J Chem Inf Model. 2014 Jul 28;54(7):1951-62. (PMID: 24850022)
Arch Virol. 2007;152(4):687-96. (PMID: 17195954)
Science. 2016 Dec 23;354(6319):1597-1600. (PMID: 27940580)
Nat Commun. 2016 Nov 15;7:13410. (PMID: 27845325)
Genome Announc. 2014 Jun 05;2(3):. (PMID: 24903869)
Curr Opin Virol. 2013 Feb;3(1):3-12. (PMID: 23352692)
Phys Rev Lett. 1996 Oct 28;77(18):3865-3868. (PMID: 10062328)
Antiviral Res. 2016 Oct;134:244-249. (PMID: 27666184)
J Chem Theory Comput. 2011 Nov 8;7(11):3768-78. (PMID: 26598269)
Science. 2016 Jul 29;353(6298):503-5. (PMID: 27386922)
Nucleic Acids Res. 1989 May 25;17(10):3889-97. (PMID: 2543956)
Curr Top Med Chem. 2010;10(1):33-45. (PMID: 19929831)
Viruses. 2013 Dec 03;5(12):2977-3006. (PMID: 24300672)
PLoS Pathog. 2015 Mar 16;11(3):e1004682. (PMID: 25775415)
Trans R Soc Trop Med Hyg. 1954 Mar;48(2):139-45. (PMID: 13157159)

001 (PROEX 23038.000509/2020-82) Coordenação de Aperfeicoamento de Pessoal de Nível Superior; 425348/2018-0 and 304935/2019-0 National Council for Scientific and Technological Development

Keywords: MM-PBSA; NS2B-NS3; Zika virus; oxyanion orifice; quantum biochemistry

0 (Protease Inhibitors)
0 (Succinates)
0 (Viral Nonstructural Proteins)
EC 3.4.- (Peptide Hydrolases)
EC 3.4.21.- (Serine Endopeptidases)

Date Created: 20220909 Date Completed: 20220912 Latest Revision: 20220919

20240513

PMC9456192

10.3390/ijms231710088

36077486