Exploring Alectinib and Irinotecan as potential human kallikrein-1 inhibitors: a drug repurposing approach for cancer and dermatological disorders

Finding effective therapies against complex diseases such as cancer is challenging. The discovery of new applications for existing compounds through drug repurposing is a promising strategy. A family of serine proteases, kallikrein-related peptidases (KLKs), including kallikrein-1 (KLK1), has diverse physiological roles. KLK1 activity is dysregulated in various complex diseases, including cancer and dermatological disorders. Currently, available KLK1 inhibitors are suboptimal due to factors such as toxicity and low specificity. In this study, we used a virtual screening approach involving molecular docking, pharmacokinetic profiling, and molecular dynamics (MD) simulations to repurposed drugs to identify potential KLK1 inhibitors. Two drugs, Alectinib (docking score −9.5 kcal/mol) and Irinotecan (docking score −9.6 kcal/mol), stood out as high-affinity binders to KLK1 with crucial interactions and appropriate pharmacokinetic profiles. The dynamic behaviour of KLK1-drug complexes was confirmed by MD simulations over 500 ns, indicating that they are stable throughout the trajectory. These elucidated drugs should be further experimentally validated to advance them to clinical application. Overall, the results highlight the potential of computational methods for finding repurposed drugs targeting KLK1 for therapeutic development against cancer and dermatological disorders.