Repurposed pharmacotherapy: targeting cathepsin L with repurposed drugs in virtual screening.

Proteolytic enzymes are closely associated with cancer and are important in different phases, including tumor growth, angiogenesis, and metastasis. Despite efforts to target matrix metalloproteases (MMPs), clinical trials have often resulted in various side effects such as musculoskeletal pain, joint stiffness, and tendinitis, making them less optimal for chronic cancer treatment. Thus, there is a need for the identification of other protease targets that would provide different approaches towards the management of cancer. Of these targets, Cathepsin L (CatL) is a lysosomal cysteine protease that has been identified as a therapeutic target that is implicated in cancer development and metastasis. In this study, we performed an integrated approach of virtual screening and molecular dynamics (MD) simulations to identify the potential inhibitors of CatL from a library of drugs that have been used for different treatments. Towards this goal, we performed virtual screening of the DrugBank database and found two repurposed drugs, Irinotecan and Nilotinib, against CatL based on their docking profiles, favorable docking scores, and specific interaction with the CatL binding pocket. MD simulations of the Irinotecan and Nilotinib bound structures with CatL were carried out, and the analysis showed that both these compounds could function as CatL inhibitors as the protein-ligand interactions were stable for 300 ns. This study highlights the robustness of these drugs bound to CatL and indicates that they could be repurposed for the treatment of cancer. These findings endorse the use of computer-based approaches for the identification of new inhibitors, and the present study will be a useful resource for future experimental research towards the targeting of CatL in cancer therapeutics.