Elucidating the mechanism of inhibitory action of novel macrocyclic compounds against ALK in non-small cell lung carcinoma: insight from molecular dynamics and virtual screening
摘要
Non-small cell lung carcinoma can be caused by the dysregulation, overexpression, or fusion of Anaplastic Lymphocytic Leukemia Kinase (ALK), which plays an essential part in cell growth and division. Several drugs have been tested against ALK overactivity, but their failure to interact effectively necessitates accelerated research efforts for the development of effective therapeutics targeting ALK. The aim of this investigation was to identify prospective macrocyclic compounds, defined as molecules containing a ring of 12 or more heavy atoms, with inhibitory potential against ALK using computational chemistry methods. To identify lead macrocyclic compounds, this work describes a five-site pharmacophore model (HHRRR_1) that showed the best survival score and PhaseHypoScore. To determine the active molecules and predict their IC50, a reliable 2D-QSAR model with an R2 of 0.9962 was used. Using docking techniques, the binding affinity of the most active compounds was analyzed in the next step. MD simulation was performed on the three most effective compounds—ML1, ML2, and ML3—to enable a comprehensive exploration of their complexes with ALK. The docking studies were validated by MD analysis results, demonstrating that all compounds form stable complexes with ALK. The pharmacokinetic properties of all compounds were assessed using ADME/tox properties, including absorption, distribution, metabolism, excretion, and toxicological characteristics. The present study provides insights into the design of novel macrocyclic compounds targeting ALK, which can be utilized to advance the development of innovative ALK inhibitors.