Potency of anti-trematode in inhibiting cathepsin-2L and cathepsin-5L of Fasciola gigantica using homology, docking, and molecular dynamics

Background: 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 Fasciola gigantica 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. Aim: This study was carried out to screen six commercial anthelmintic drugs against cathepsin-2L (FhCL-2) and cathepsin 5L (FhCL-5) using in silico and molecular dynamics approach. Methods: 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". Results: Molecular docking results showed that all tested ligands had affinity for FhCL-2 and FhCL-5. The best triangle Gbinding value for FhCL-2 was clorsulon ligand (-15.21 kcal/mol) with pKi of 32.25 mu M, which was significantly different compared to other drugs (p < 0.05). For FhCL-5, the best triangle Gbinding value was closantel ligand (-14.88 kcal/ mol) with pKi of 31.51 <mu>M, significantly different from other drugs tested (p < 0.05). The results of the molecular dynamics simulation for the two ligands showed a strong and stable interaction at their respective binding sites. Conclusion: All of the tested anti-trematode ligands had potency as inhibitors for FhCL-2 and FhCL-5 enzymes of F. gigantica, 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.