Pharmacophore generation, atom-based 3D-QSAR, docking, and virtual screening studies of p38-α mitogen activated protein kinase inhibitors: pyridopyridazin-6-ones (part 2)

Abstract

Pharmacophore generation, atom-based 3D-QSAR, docking, and virtual screening studies of p38-α mitogen activated protein kinase inhibitors: pyridopyridazin-6-ones (part 2) Sujit G Bhansali, Vithal M KulkarniDepartment of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Pune, Maharashtra, IndiaAbstract: p38-α mitogen-activated protein kinase (MAPK) is a serine/threonine kinase activated by environmental stimuli, like stress, and by various proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-1β. Excessive production of tumor necrosis factor-α and interleukin-1 β may lead to various diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Hence, inhibition of p38-α MAPK could be a novel approach for the development of new anti-inflammatory agents. In this study, a combination of pharmacophore generation, an atom-based three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and virtual screening was performed for a series of pyridopyridazin-6-ones exhibiting p38-α MAPK inhibition activity. A five-point pharmacophore (AAAHR), ie, three hydrogen bond acceptors (AAA), one hydrophobic (H) group, and one aromatic ring (R) was obtained. A statistically significant 3D-QSAR model was obtained using this pharmacophore hypothesis with a good correlation coefficient (R2=0.91) and a high Fisher ratio (F=90.3) for the training set of 47 compounds. The predictive power of the model generated was found to be significant, and was confirmed by the high value of the cross-validated correlation coefficient (q2=0.80) and Pearson's R (0.90) for the test set of 16 compounds. Further, the docking study revealed the binding orientations of the active ligand on the amino acid residues Valine 30 (Val30), Glycine 31 (Gly31), Lysine 53 (Lys53), Leucine 75 (Leu75), Aspartic acid 88 (Asp88), Methionine 109 (Met109) of p38-α MAPK at the active site. The results of this ligand-based pharmacophore hypothesis and atom-based 3D-QSAR provide detailed structural insights and highlight the important binding features between pyridopyridazin-6-ones and p38-α MAPK. These findings may provide useful guidelines for rational design of compounds with better p38-α MAPK activity.Keywords: pyridopyridazin-6-ones, p38-α mitogen-activated protein kinase, pharmacophore, three-dimensional quantitative structure activity relationship, docking, virtual screening