Biotechnology & Molecular Biology Laboratory, State University of Ceará, Fortaleza 60714-903, Brazil.
Federal Institute of Education, Science and Technology of Ceará, Campus Horizonte, Horizonte 62884-105, Brazil.
Int J Mol Sci. 2022 Sep 3;23(17):10088. doi: 10.3390/ijms231710088.
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.
寨卡病毒蛋白酶 NS2B-NS3 具有一个结合位点，该结合位点由 H51-D75-S135 三联体参与形成，呈现出两种形式，即活性和非活性。研究表明，非活性构象是设计抑制剂的一个很好的目标。在本文中，我们评估了与抑制剂苯甲酸（5YOD）和苯并咪唑-1-基甲醇（5H4I）的共结晶结构。我们应用了一个由两个步骤组成的方案：首先，进行经典分子力学能量最小化，然后进行经典分子动力学，以获得稳定的分子几何形状；其次，优化/松弛的几何形状用于量子生物化学和分子力学/泊松-玻尔兹曼表面面积（MM-PBSA）计算，以估计配体与结合口袋中每个氨基酸残基的相互作用。我们表明，量子水平的结果确定了稳定 5YOD 和 5H4I 复合物的关键残基，这与先前发表的实验数据相匹配。然而，MM-PBSA 模拟并没有取得同样的成功。量子生物化学方法的应用似乎更有希望设计作用于 NS2B-NS3 的新型抑制剂。
