title: An integrated molecular modeling approach for in silico design of new tetracyclic derivatives as ALK inhibitors.
abstract: Anaplastic lymphoma kinase (ALK), a promising therapeutic target for treatment of human cancers, is a receptor tyrosine kinase that instigates the activation of several signal transduction pathways. In the present study, in silico methods have been employed in order to explore the structural features and functionalities of a series of tetracyclic derivatives displaying potent inhibitory activity toward ALK. Initially docking was performed using GLIDE 5.6 to probe the bioactive conformation of all the compounds and to understand the binding modes of inhibitors. The docking results revealed that ligand interaction with Met 1199 plays a crucial role in binding of inhibitors to ALK. Further to establish a robust 3D-QSAR model using CoMFA and CoMSIA methods, the whole dataset was divided into three splits. Model obtained from Split 3 showed high accuracy ([Formula: see text] of 0.700 and 0.682, [Formula: see text] of 0.971 and 0.974, [Formula: see text] of 0.673 and 0.811, respectively for CoMFA and CoMSIA). The key structural requirements for enhancing the inhibitory activity were derived from CoMFA and CoMSIA contours in combination with site map analysis. Substituting small electronegative groups at Position 8 by replacing either morpholine or piperidine rings and maintaining hydrophobic character at Position 9 in tetracyclic derivatives can enhance the inhibitory potential. Finally, we performed molecular dynamics simulations in order to investigate the stability of protein ligand interactions and MM/GBSA calculations to compare binding free energies of co-crystal ligand and newly designed molecule N1. Based on the coherence of outcome of various molecular modeling studies, a set of 11 new molecules having potential predicted inhibitory activity were designed.
authors.affiliation: a Department of Chemistry , University College of Science, Osmania University , Hyderabad , India and.
authors.forename: Saikiran Reddy
authors.initials: SR
authors.lastname: Peddi
authors.affiliation: b Department of Chemistry , Nizam College , Hyderabad , India.
authors.forename: Sree Kanth
authors.initials: SK
authors.lastname: Sivan
authors.affiliation: a Department of Chemistry , University College of Science, Osmania University , Hyderabad , India and.
authors.forename: Vijjulatha
authors.initials: V
authors.lastname: Manga
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation / Q000187:drug effects; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D021281:Quantitative Structure-Activity Relationship; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: 3D-QSAR; Anaplastic lymphoma kinase; molecular docking; molecular dynamics simulation; site map analysis