Computational Elucidation of Potent Ligands Targeting Recalcitrant ALK G1202R‐Associated Double Mutations Underlying Lorlatinib Resistance

Abstract

Targeting ALK has become a viable therapeutic strategy in non‐small cell lung cancer (NSCLC) following the discovery of the EML4‐ALK fusion. Several inhibitors were developed which improved the patient's outcomes; however, the emergence of drug resistance limits the treatment and poses significant challenges. The sequential use of inhibitors led to the development of compound mutations, predominantly G1202R‐based double mutations. In this study, we analyzed two highly recalcitrant G1202R‐paired double mutations – G1202R+L1196M and G1202R+S1206Y detected in EML4‐ALK variant 3 patients in cis following lorlatinib therapy. This study employs an integrated approach, including virtual screening, ADMET analysis, molecular docking, and simulations, to identify potential lead compounds. We identified two compounds, CID 118002992 and CID 155425575, from virtual screening with better characteristics. Molecular docking revealed that CID 155425575 exhibited stronger binding affinity with G1202R+L1196M (−9.33 kcal/mol) and G1202R+S1206Y (−9.29 kcal/mol). MD simulations were performed for 200 ns to investigate the stability and conformational changes of ALK double mutations and WT‐ALK in the presence of ligands. Notably, CID 155425575 showed enhanced structural stability and compactness and demonstrated the most favorable binding free energies (−103.250 ± 15.928 kJ/mol and −95.886 ± 11.813 kJ/mol), emerging as a promising lead candidate against the G1202R‐paired double mutations.