Atom Based 3D-QSAR, Molecular Docking and Density Functional Theory Approaches to Identify Novel JNK-1 Inhibitor

C-Jun-N-terminal kinase -1 (JNK -1) is a seriene/threonine kinase protein and a member of mitogen activated protein family (MAP- Kinase). The activation of JNK-1 leads to cell proliferation, cell death, DNA repair and metabolism. In our study we aim in creating a novel JNK-1 inhibitor.

Various computational techniques like 3D-atom based QSAR analysis; pharmacophore based virtual screening; molecular docking and Density functional theory approaches are utilised to obtain novel JNK-1 inhibitor.

Pharmacophores with pharmacophoric features as two hydrogen bond acceptors (A), one hydrogen bond donor (D), one hydrophobic (H) and one aromatic ring (R) are generated. Amongst the generated pharmacophore hypothesis, AADHR.6 was found to have good survival score of 3.214 and is used to derive atom based 3D - QSAR model. The obtained 3D - QSAR model has excellent squared correlation coefficient value (R2= 0.9272) and a good fisher ratio (F= 273.9). The reliability and robustness of the chosen model is validated both internally and externally to obtain good statistical results. The model AADHR.6 is used in virtual screening of Zinc and NCI databases for potential inhibitors. Resulting hit compounds from virtual screening are then subjected to docking and Density Functional Theory (DFT) studies.

Both docking and DFT studies brings out two lead compounds with good inhibitory activity against the receptor. Thus the work presents a novel JNK - 1 inhibitor that can serve as potential therapeutics for the treatment of various diseases associated with abnormal JNK -1 functioning.