title: Molecular docking, 3D QSAR and dynamics simulation studies of imidazo-pyrrolopyridines as janus kinase 1 (JAK 1) inhibitors.
abstract: Janus kinase 1 (JAK 1) plays a critical role in initiating responses to cytokines by the JAK-signal transducer and activator of transcription (JAK-STAT). This controls survival, proliferation and differentiation of a variety of cells. Docking, 3D quantitative structure activity relationship (3D-QSAR) and molecular dynamics (MD) studies were performed on a series of Imidazo-pyrrolopyridine derivatives reported as JAK 1 inhibitors. QSAR model was generated using 30 molecules in the training set; developed model showed good statistical reliability, which is evident from r2ncvand r2loovalues. The predictive ability of this model was determined using a test set of 13 molecules that gave acceptable predictive correlation (r2Pred) values. Finally, molecular dynamics simulation was performed to validate docking results and MM/GBSA calculations. This facilitated us to compare binding free energies of cocrystal ligand and newly designed molecule R1. The good concordance between the docking results and CoMFA/CoMSIA contour maps afforded obliging clues for the rational modification of molecules to design more potent JAK 1 inhibitors.
authors.affiliation: Department of Chemistry, University College of Science, Osmania University, Hyderabad 07, India.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Itteboina
authors.affiliation: Department of Chemistry, University College of Science, Osmania University, Hyderabad 07, India.
authors.forename: Srilata
authors.initials: S
authors.lastname: Ballu
authors.affiliation: Department of Chemistry, University College of Science, Osmania University, Hyderabad 07, India.
authors.forename: Sree Kanth
authors.initials: SK
authors.lastname: Sivan
authors.affiliation: Department of Chemistry, University College of Science, Osmania University, Hyderabad 07, India. Electronic address: vijjulathamanga@gmail.com.
authors.forename: Vijjulatha
authors.initials: V
authors.lastname: Manga
mesh_terms: D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; D053613:Janus Kinase 1
keywords: CoMFA; CoMSIA; JAK; MD; PLS; SP