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

Autor: Valdir Ferreira de Paula Junior, Mauricio Fraga van Tilburg, Pablo Abreu Morais, Francisco Franciné Maia Júnior, Elza Gadelha Lima, Victor Tabosa dos Santos Oliveira, Maria Izabel Florindo Guedes, Ewerton Wagner Santos Caetano, Valder Nogueira Freire
Rok vydání: 2022
Předmět:
Zdroj: International Journal of Molecular Sciences; Volume 23; Issue 17; Pages: 10088
ISSN: 1422-0067
DOI: 10.3390/ijms231710088
Popis: 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.
Databáze: OpenAIRE
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