Discovery of novel anaplastic lymphoma kinase inhibitors with enhanced binding interactions for non-small cell lung cancer via in silico approaches and retrospective experimental data support.

Anaplastic lymphoma kinase (ALK) has emerged as a critical therapeutic target in non-small cell lung cancer (NSCLC) treatment due to its central role in oncogenic signaling pathways. Based on the detailed analysis of the mechanism of Brigatinib, an in silico approach was performed to discover novel ALK inhibitors with enhanced binding interactions. Structure-based virtual screening of the ChEMBL database yielded 16 hits with favorable drug-likeness and predicted affinity toward ALK. And 5 compounds (C321, C475, C487, C444 and C479) were prioritized as candidates with favorable pharmacokinetic properties and low predicted toxicity risk by ADMET profiling. All-atom molecular dynamics simulations over 500 ns trajectories demonstrated that the key conformational transitions of protein-ligand complexes were stable through essential dynamics analysis. Density functional theory (DFT) analyses further uncover distinct electronic configuration patterns and interaction geometries among the candidates, revealing that distinct binding strategies are employed. Specifically, the hydrogen bond dominated anchoring (e.g., C444, C479), van der Waals driven hydrophobic encapsulation (e.g., C321, C475, C487), and electrostatic complementarity (e.g., C444) all contribute differentially to the overall binding affinity. Notably, C479 exhibited in vitro inhibitory activity comparable to Brigatinib. All the results indicate that the candidate compounds not only possess inhibitory activity similar to that of Brigatinib, but may also help diversify the existing repertoire of ALK-targeted agents and provide additional options for NSCLC research.