Similar Kinases, Distinct Hits: In Silico Repurposing of FDA-Approved Drugs for ALK and ROS1

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INTRODUCTION: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases, with protein rearrangements on ALK and ROS1 kinases defining clinically relevant subgroups [1,2]. Drug repurposing offers an opportunity to investigate new therapeutic applications for approved drugs, potentially reducing time and cost associated with conventional drug development [3]. This study aimed to identify potential repurposing candidates for ALK and ROS1 by screening a library of FDA-approved drugs against their ATP-binding pockets [4,5]. METHODOLOGY: Molecular docking (AutoDock Vina) was performed for ALK and ROS1 using 2,162 FDA-approved drugs from the Cheminformatic Tools and Databases for Pharmacology. For each kinase, 10 protein-ligand complexes were parameterized with CHARMM-GUI/CHARMM36 and submitted to molecular dynamics (MD) simulations (GROMACS), alongside ATP and crizotinib as substrate and inhibitor references, respectively. Binding persistence was evaluated by the distance between ligand center-of-mass (COM) and protein binding pocket. RESULTS: Docking scores reached −10.653 kcal/mol for ALK and −10.771 kcal/mol for ROS1, compared with −8.035 and −8.790 kcal/mol for crizotinib, respectively. Based on docking and MD simulations, two candidates were prioritized for ALK and seven for ROS1. Prioritized candidates remained within the binding pocket, with maximum COM-distance changes of 0.70 nm for ALK and 0.65 nm for ROS1, while crizotinib showed changes of 0.793 nm and 0.991 nm, respectively. CONCLUSION: The in silico results support the selection of FDA-approved drugs as promising repurposing candidates. Despite structural similarity of ALK and ROS1 kinase domains, different screening rankings highlight the importance of specific binding when prioritising candidates for experimental validation.

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