title: Pharmacophore generation and atom-based 3D-QSAR of novel quinoline-3-carbonitrile derivatives as Tpl2 kinase inhibitors.
abstract: Tumour progression locus-2 (Tpl2) is a serine/threonine kinase, which regulates the expression of tumour necrosis factor α. The article describes the development of a robust pharmacophore model and the investigation of structure-activity relationship analysis of quinoline-3-carbonitrile derivatives reported for Tpl2 kinase inhibition. A five point pharmacophore model (ADRRR) was developed and used to derive a predictive atom-based 3-dimensional quantitative structure activity relationship (3D-QSAR) model. The obtained 3D-QSAR model has an excellent correlation coefficient value (r(2)= 0.96), Fisher ratio (F = 131.9) and exhibited good predictive power (q(2) = 0.79). The QSAR model suggests that the inclusion of hydrophobic substituents will enhance the Tpl2 kinase inhibition. In addition, H-bond donating groups, negative ionic groups and electron withdrawing groups positively contribute to the Tpl2 kinase inhibition. Further, pharmacophoric model was validated by the receiver operating characteristic curve analysis and was employed for virtual screening to identify six potential Tpl2 kinase inhibitors. The findings of this study provide a set of guidelines for designing compounds with better Tpl2 kinase inhibitory potency.
authors.affiliation: School of Biotechnology, National Institute of Technology Calicut, Calicut, India.
authors.forename: Mahesh Kumar
authors.initials: MK
authors.lastname: Teli
authors.forename: G K
authors.initials: GK
authors.lastname: Rajanikant
mesh_terms: D016208:Databases, Factual; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011804:Quinolines; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human