Molecular docking, 3D QSAR and dynamics simulation studies of imidazo-pyrrolopyridines as janus kinase 1 (JAK 1) inhibitors. (October 2016)

• Record Type: Journal Article
• Authors: Itteboina, Ramesh; Ballu, Srilata; Sivan, Sree Kanth; Manga, Vijjulatha
• Is Part Of: Computational biology and chemistry. Volume 64(2016)
• Page Start: 33
• Page End: 46
• Publication Date: 2016-10
• Subjects: CoMFA -- CoMSIA -- PLS -- JAK -- SP -- MD; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2016.04.009
• Languages: English
• ISSNs: 1476-9271

Abstract

Graphical 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. Highlights: CoMFA, CoMSIA models were developed for a series of 43 Imidazo- pyrrolopyridine derivatives. Molecular docking method was used to analyze possible interactions between receptors and the compounds. Results of the docking studies and molecular dynamics simulations complement each other. Seven derivatives as potential candidates of JAK1 inhibitors with good predicted activities were designed. 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 r 2 ncv and r 2 loo values. The predictive ability of this model was determined using a test set of 13 molecules that gave acceptable predictive correlation (r 2 Pred ) 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.