Computational drug repurposing reveals Alectinib as a potential lead targeting Cathepsin S for therapeutic developments against cancer and chronic pain

Mohammed Alrouji¹Mohammed S Alshammari¹Sharif Alhajlah¹Syed Tasqeeruddin²Dinislam Khuzin³Anas Shamsi⁴Saleha Anwar^4*

• ¹Shaqra University, Shaqra, Saudi Arabia
• ²King Khalid University, Abha, Saudi Arabia
• ³Baskirskij gosudarstvennyj medicinskij universitet, Ufa, Russia
• ⁴Ajman University, Ajman, United Arab Emirates

Cathepsin S (CathS) is a cysteine protease known to play a role in extracellular matrix (ECM) re-modelling, antigen presentation, immune cells polarisation, and cancer progression and chronic pain pathophysiology. CathS also causes an immunosuppressive environment in solid tumors and is involved in nociceptive signaling. Although several small-molecule inhibitors with favorable in vivo properties have been developed, their clinical utility is limited due to resistance, off-target effects, and suboptimal efficacy. Therefore, alternative therapeutic strategies are urgently needed. In the present study, we utilized an integrated virtual screening protocol to screen 3,500 commercially available FDA‑approved drug molecules from DrugBank against the CathS crystal structure, based on which drug‑likeness profile and interaction studies were performed to filter putative candidates. Alectinib was found to be a top hit and had significant interactions with the important active‑site residues His278 and Cys139. PASS predictions suggested relevant anticancer and anti‑pain activities for Alectinib in reference to the control inhibitor Q1N. Later, 500‑ns molecular dynamics simulations under the CHARMM36 condition revealed that the CathS-Alectinib complex maintained its structural stability, as indicated by conformational parameters, hydrogen‑bond persistence, and essential dynamics analyses. Further MM‑PBSA calculations also confirmed a favorable binding free energy (ΔG –20.16 ± 2.59 kcal/mol) dominated by the van der Waals and electrostatic contributions. These computational findings suggest that Alectinib may have potential as a repurposed CathS inhibitor, warranting further experimental testing in relevant cancer and chronic pain models. Notably, these results are based solely on computational analysis and require empirical validation.