Density Functional Theory and Molecular Simulation Studies for Prioritizing Anaplastic Lymphoma Kinase Inhibitors.

摘要: Targeting anaplastic lymphoma kinase (ALK) is one of the important treatment strategies for non-small cell lung cancer (NSCLC). In present perspective, multidimensional approaches were used identification ALK inhibitors. Initially, an e-pharmacophore model was generated using PHASE algorithm and as a 3D query to screen 468,200 molecules ASINEX database. Prior screening process, evaluated its significance ability differentiate actives from inactives, enrichment analysis. Subsequently, hierarchical docking protocol binding free energy calculations instigated GLIDE Prime module, respectively. Further, pharmacokinetic/pharmacodynamics (PK/PD) properties toxicities hit compounds envisaged respectively QikProp program, Osiris explorer, Protox-II algorithm. These retrieved two hits namely BAS 00137817 00680055 with acceptable absorption, distribution, metabolism, excretion toxicity (ADMET) higher affinity towards protein. Additionally, density functional theory molecular dynamics simulations performed validate inhibitory activity lead compounds. It noteworthy mention that all constitute particular scaffolds which play major role in downregulation some ALK-positive pathways. We speculate outcomes this research are substantial prominence rational designing novel efficacious