Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China.
Int J Mol Sci. 2019 Mar 26;20(6):1516. doi: 10.3390/ijms20061516.
β--Acetyl-d-hexosaminidase from (OHex1) is a new target for the design of insecticides. Although some of its inhibitors have been found, there is still no commercial drug available at present. The residence time of the ligand may be important for its pharmacodynamic effect. However, the unbinding routes of ligands from OHex1 still remain largely unexplored. In the present study, we first simulated the six dissociation routes of -trimethyl-d-glucosamine-chitotriomycin (TMG-chitotriomycin, a highly selective inhibitor of OHex1) from the active pocket of OHex1 by steered molecular dynamics simulations. By comparing the potential of mean forces (PMFs) of six routes, Route 1 was considered as the most possible route with the lowest energy barrier. Furthermore, the structures of six different states for Route 1 were snapshotted, and the key amino acid residues affecting the dissociated time were analyzed in the unbinding pathway. Moreover, we also analyzed the "open⁻close" mechanism of Glu368 and Trp448 and found that their conformational changes directly affected the dissociation of TMG-chitotriomycin. Our findings would be helpful to understanding and identifying novel inhibitors against OHex1 from virtual screening or lead-optimization.
β--乙酰基-d-己糖苷酶来自 （OHex1）是设计杀虫剂的新靶标。尽管已经发现了一些抑制剂，但目前仍没有商业药物可用。配体的停留时间可能对其药效有重要影响。然而，OHex1 配体的非结合途径在很大程度上仍未得到探索。在本研究中，我们首先通过定向分子动力学模拟模拟了 -三甲基-d-葡萄糖胺壳三霉素（TMG-壳三霉素，OHex1 的高度选择性抑制剂）从 OHex1 活性口袋中的六种解离途径。通过比较六种途径的平均力势（PMF），Route 1 被认为是能量壁垒最低的最可能途径。此外，我们还对 Route 1 的六种不同状态的结构进行了快照，并分析了非结合途径中影响解离时间的关键氨基酸残基。此外，我们还分析了 Glu368 和 Trp448 的“开-关”机制，发现它们的构象变化直接影响 TMG-壳三霉素的解离。我们的研究结果将有助于从虚拟筛选或先导优化中理解和识别针对 OHex1 的新型抑制剂。
