Vanda Henni, Athaillah Farida, Sari Wahyu Eka, Frengki Frengki, Nurliana Nurliana, Hambal Muhammad
Pharmacology Department, Faculty of Veterinary Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia.
Parasitology Department, Faculty of Veterinary Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia.
Open Vet J. 2024 Nov;14(11):2754-2761. doi: 10.5455/OVJ.2024.v14.i11.4. Epub 2024 Nov 30.
Cathepsin-L (FhCL) is a group of enzymes that most flukes express and secreted significantly in parasite-host interactions. Researches are focusing on antigens released by as one of the keys to understanding immunologic pathways in parasite infection and targets for anthelmintics. Efforts to suppress FhCL function through vaccination or therapy using anthelmintic drugs are key factors in controlling field-level trematode infections. A molecular docking method can be used to observe the interaction between FhCL and some anthelmintic drugs to better understand the effect of these anthelmintics on FhCL. Furthermore, it is necessary to carry out molecular dynamics methods to observe the dynamic pattern of the interaction of the enzyme-ligand when the dynamics simulation is in progress.
This study was carried out to screen six commercial anthelmintic drugs against cathepsin-2L (FhCL-2) and cathepsin 5L (FhCL-5) using and molecular dynamics approach.
The three-dimensional (3D) crystal structure of FhCL-2 and FhCL-5 enzymes were constructed based on the crystal structure of ProCathepsin 1L (pdb id. 2O6X) as a template, while six anthelmintic agents ("SMILES" format) were downloaded from PubChem and converted to 3D format using the MOE Builder tool. The enzyme modeling results were evaluated using the "Ramachandran Plot".
Molecular docking results showed that all tested ligands had affinity for FhCL-2 and FhCL-5. The best ∆Gbinding value for FhCL-2 was clorsulon ligand (-15.21 kcal/mol) with pKi of 32.25 µM, which was significantly different compared to other drugs ( < 0.05). For FhCL-5, the best ∆Gbinding value was closantel ligand (-14.88 kcal/mol) with pKi of 31.51 µM, significantly different from other drugs tested ( < 0.05). The results of the molecular dynamics simulation for the two ligands showed a strong and stable interaction at their respective binding sites.
All of the tested anti-trematode ligands had potency as inhibitors for FhCL-2 and FhCL-5 enzymes of and the best candidate for FhCL-2 was clorsulon, and for FhCL-5 was closantel. This finding is useful as an approach to develop novel drugs from existing drugs as inhibitors for FhCL-2 and FhCL-5 enzymes.
组织蛋白酶-L（FhCL）是大多数吸虫在寄生虫与宿主相互作用过程中大量表达并分泌的一组酶。作为理解寄生虫感染免疫途径的关键因素之一以及驱虫药的作用靶点，对其释放的抗原的研究备受关注。通过疫苗接种或使用驱虫药进行治疗来抑制FhCL功能，是控制田间吸虫感染的关键因素。分子对接方法可用于观察FhCL与某些驱虫药之间的相互作用，以便更好地了解这些驱虫药对FhCL的作用效果。此外，有必要进行分子动力学方法来，以动力学模拟时观察酶-配体相互作用的动态模式。
本研究旨在使用分子对接和分子动力学方法筛选六种市售驱虫药对组织蛋白酶-2L（FhCL-2）和组织蛋白酶5L（FhCL-5）的作用。
以ProCathepsin 1L（pdb编号2O6X）的晶体结构为模板构建FhCL-2和FhCL-5酶的三维（3D）晶体结构，同时从PubChem下载六种驱虫剂（“SMILES”格式），并使用MOE Builder工具将其转换为3D格式。使用“拉氏图”评估酶建模结果。
分子对接结果表明，所有测试配体对FhCL-2和FhCL-5均具有亲和力。FhCL-2的最佳∆G结合值是氯磺隆配体（-15.21 kcal/mol），pKi为32.25 µM，与其他药物相比有显著差异（P<0.0）。对于FhCL-5，最佳∆G结合值是氯氰碘柳胺配体（-14.88 kcal/mol），pKi为31.51 µM，与其他测试药物有显著差异（P<0.05）。两种配体的分子动力学模拟结果显示它们在各自结合位点有强烈且稳定的相互作用。
所有测试的抗吸虫配体对FhCL-2和FhCL-5酶均有作为抑制剂的潜力，FhCL-2的最佳候选药物是氯磺隆，FhCL-5的最佳候选药物是氯氰碘柳胺。这一发现有助于从现有药物开发新型药物作为FhCL-2和FhCL-5酶的抑制剂。
