title: Molecular dynamics and pharmacophore modelling studies of different subtype (ALK and EGFR (T790M)) inhibitors in NSCLC.
abstract: Extensively validated 3D pharmacophore models for ALK (anaplastic lymphoma kinase) and EGFR (T790M) (epithelial growth factor receptor with acquired secondary mutation) were developed. The pharmacophore model for ALK (r2= 0.96, q2= 0.692) suggested that two hydrogen bond acceptors and three hydrophobic groups arranged in 3-D space are essential for the binding affinity of ALK inhibitors. Similarly, the pharmacophore model for EGFR (T790M) (r2= 0.92, q2= 0.72) suggested that the presence of a hydrogen bond acceptor, two hydrogen bond donors and a hydrophobic group plays vital role in binding of an inhibitor of EGFR (T790M). These pharmacophore models allowed searches for novel ALK and EGFR (T790M) dual inhibitors from multiconformer 3D databases (Asinex, Chembridge and Maybridge). Finally, the eight best hits were selected for molecular dynamics simulation, to study the stability of their complexes with both proteins and final binding orientations of these molecules. After molecular dynamics simulations, one hit has been predicted to possess good binding affinity for both ALK and EGFR (T790M), which can be further investigated for its experimental in-vitro/in-vivo activities.
authors.affiliation: a Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research , Punjabi University , Patiala , Punjab , India.
authors.forename: P K
authors.initials: PK
authors.lastname: Singh
authors.affiliation: a Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research , Punjabi University , Patiala , Punjab , India.
authors.forename: O
authors.initials: O
authors.lastname: Silakari
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D055808:Drug Discovery / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006131:Growth Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011487:Protein Conformation; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; EGFR (T790M); lung cancer; molecular dynamics; pharmacophore modelling