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P38&#x3b4; Mitogen activated protein kinase is a serine/threonine protein kinase that participates in signaling cascades, mediating cellular responses to cytokinines, UV radiation, hyperosmotic stress, inducing keratinocyte differentiation and regulating apoptosis. Over expression of p38&#x3b4; leads to tumor development by impairing the ERK1/2 &#x2013;AP1 pathway that is critically linked to the control of cell proliferation and tumorigenesis on skin which was experimentally proven in knockout mice. Therefore, herein, a computational approach was undertaken to design novel inhibitors against p38delta for effective cancer therapy. The tertiary structure of p38&#x3b4; was retrieved from a protein databank and active sites were predicted from CASTP and site finder and were optimized by applying OPLS force field in Maestro v9.0. Four p38&#x3b4; specific inhibitors 4-(4-(2-(cyclopentylamino)pyrimidin-4-yl)-1H-pyrazol-3-yl)cyclohexanol,(R)-2-(sec-butylamino)-N-(2-methyl-5-(methylcarbamoyl)phenyl)thiazole-5-carboxamide, BIRB796 and ANP were selected from the literature for high throughput screening against one million compounds from the Ligand.Info metadatabase to generate an in-house library of 1515 structural analogs.  The ligand library was prepared using LigPrep and compounds with ADME violations were discarded from the dataset. The candidates from the optimized ligand dataset were docked into the active site of p38&#x3b4; through sequential application of Glide HTVS, SP and XP methods that penalizes more stringently for minor steric classes subsequently. Through comparative analysis of binding orientations and the XP G-score of the protein-ligand docking complexes with published inhibitor data, 4 lead molecules with the lowest docking scores(-12.12,-10.06,-9.47 and-9.36) are proposed to be considered as potential inhibitors of p38&#x3b4;. The lead molecules would be highly encouraging for future cancer therapy if tested in animal models

Identification of potent inhibitors for p38δ MAPkinase of human through in silico analysis