Designing Potent Inhibitors Of Human p38γ For Effective Breast Cancer Therapy
Authors: Pradeep Natarajan , Pradhan Dibyabhaba , Umamaheswari Amineni 
Published: October 2010

AbstractOncogenic constitutive enzyme human p38γ is a serine/threonine protein kinase, activated through phosphorylation by environmental stress and pro-inflammatory cytokines responses. Breast cancer, hepatoma, colon cancer, atherosclerotic lesion (coronary artery lesion / hardening of artery), hypertension and inflammations are some of the diseases caused by human p38γ due to over expression. Over expression of the protein in turn induces anti-apoptosis and inflammatory responses, increased malignant transformation and cell differentiation. Thus, designing potent inhibitors against p38γ would be highly practicable for development of novel means of breast cancer therapeutics. Extensive preclinical data and proteomic analysis support the involvement of human p38γ protein in MAPK signaling pathway in cancer biology and it can be used as a potential therapeutic target in human cancers. Phylogenetic analysis delineated the close relationship of human p38γ with other 27 human oncogenes involved in cell signaling pathway. The pathway analysis also clearly explains the formation of anti-apoptosis and inflammatory responses. It is relevant and attractive drug target for cancer diseases. Computational method for drug designing was practiced here to explore lead molecules targeting human p38γ. Amino acid residues viz. Lys56, Pro110, Met112, Asp115, Gly157, Asn158, Asp171 and water molecules viz. W2111, W2039 and W2152 were observed to have important role in ligand binding in human p38γ crystal structure (PDB ID: 1CM8) through PyMol. BIRB796, SB202190, 3-[4-[2-(cyclopentylamino) pyrimidin-4-yl]-1H-pyrazol-5-yl] cyclohexan-1-ol, (R)-2-(sec-butyl amino)-N-(2-methyl-5-(methyl carbamoyl) phenyl) thiazole-5-carboxamide are the four published inhibitors and PDB ligand phosphoaminophosphonic acid-adenylate ester (ANP) were selected and an in house library of 1909 lead molecules was generated through Ligand.info Metadata base. Maestro 9.0 virtual screening protocol was practiced to determine the binding affinity of 1909 compounds into p38γ active site grid generated around the centroid of binding site residues. The Glide computational docking method of Maestro virtual screening protocol had generated 18 lead molecules with good binding affinity towards human p38γ. The best ranked lead molecule 3-DEAZA-ADENOSINE (Lead ‘1’) docked with least docking score -10.22 kcal/ mol representing better binding affinity than the existing published inhibitors and other 17 lead molecules proposed against human p38γ in the present study. Analysis of binding orientations of the docking complex revealed four amino acid residues Pro110, Met112, Asp115, Asn158 and W2039 of active site were directly involved in formation of hydrogen bond network which complements well with previous crystallographic reports of human p38γ –ANP inhibitor complex. 3-DEAZA-ADENOSINE was also observed to be involved in good van der Waal interaction with Lys56 that is highly important for ATP binding and subsequent activation of human p38γ. Thus, 3-DEAZA-ADENOSINE might be encouraging for new directions as a drug for human p38γ protein for the novel class treatment of breast cancer.