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7358281 
Journal Article 
3D-QSAR studies on disubstituted dibenzosuberone derivatives as p38 alpha MAP kinase inhibitors using CoMFA and COMSIA 
Balasubramanian, PK; Balupuri, A; Cho, S 
2016 
1 
Medicinal Chemistry Research
ISSN: 1054-2523
EISSN: 1554-8120 
25 
10 
2349-2359 
WOS:000386697200024 
The p38 mitogen-activated protein kinases belong to the mitogen-activated protein kinase superfamily. They are strongly activated by different stress signals and inflammatory cytokines. p38 alpha mitogen-activated protein kinase is broadly expressed in most cell types and plays an important role in the coordination of the cellular responses such as proliferation, differentiation & survival. The role of p38 alpha in various cancers and cellular functions makes it an interesting kinase drug target. In the present study, a series of recently published disubstituted dibenzosuberones derivatives were taken as p38 alpha inhibitors and three-dimensional quantitative structure-activity relationship study was performed. A reasonable Comparative Molecular Field Analysis (q (2) = 0.689, NOC = 6, r (2) = 0.942) and Comparative Molecular Similarity Indices Analysis (q (2) = 0.645, NOC = 6, r (2) = 0.921) models were developed. All the developed models were validated using external test set, bootstrapping, progressive sampling and rm (2) metric calculations. The validation of models showed acceptable statistical values and proved to be predictive and robust. The contour map analysis revealed the important insight on favorable substituents to increase the potency of the compounds. Negative substitution near the oxygen atom of R-1 position and hydrophobic & hydrogen bond acceptor groups near the phenyl ring of R-1 position could enhance the activity. Likewise, positive hydrophobic substitution near the phenyl ring at R-3 position favors the increase in the inhibitory activity. Our finding could be helpful to design a more potent derivative of p38 alpha kinase inhibitors in future. 
MAPK; p38 alpha Kinase; CoMFA; COMSIA; Inhibitors; Dibenzosuberones