Journal of Computational Methods in Molecular Design, 2012, 2 (3):107-121 Scholars Research Library (http://scholarsresearchlibrary.com/archive.html) ISSN : 2231- 3176 CODEN (USA): JCMMDA 107 Available online at www.scholarsresearchlibrary.com 2D and 3D QSAR using kNN-MFA method of pyrazolyl-thiazolinone derivatives as potential EGFR and HER-2 kinase inhibitors Shraddha T. Thombare, Steffi I. Gonsalves and Anwar R. Shaikh * Bhujbal Knowledge City, MET’s Institute of Pharmacy, Adgaon, Nashik-422003, India _____________________________________________________________________________________________ ABSTRACT Quantitative structure–activity relationship (QSAR) analysis for recently synthesized pyrazolyl-thiazolinone derivatives was studied for their EGFR and HER-2 kinase inhibitory activities. The statistically significant 2D- QSAR models (r 2 = 0.9086; q 2 = 0.8370; F test = 49.6789; r 2 se = 0.1242; q 2 se = 0.1675; pred_r 2 = 0.8086; pred_r 2 se = 0.1934 and r 2 = 0.9163; q 2 = 0.8702; F test 54.7057; r 2 se= 0.0820; q 2 se=0.1020; pred_r 2 = 0.8249; pred_r 2 se = 0.1195) were developed using molecular design suite (VLifeMDS 4.1). The study was performed with 36 compounds (data set) using sphere exclusion (SE) algorithm, random selection and manual selection methods used for the division of the data set into training and test set. Partial least square regression (PLSR) methodology with stepwise (SW) forward-backward variable selection method was used for building the QSAR models. The results of the 2D-QSAR models were further compared with 3D-QSAR models generated by kNN-MFA, (k-Nearest Neighbor Molecular Field Analysis) investigating the substitutional requirements for the favorable inhibitory activity for EGFR and HER-2 in tumor growth and providing useful information in the characterization and differentiation of their binding sites. The results derived may be useful in further designing novel EGFR and HER-2 kinase inhibitors prior to synthesis. Keywords: pyrazolyl-thiazolinone, EGFR, HER-2, antitumor, quantitative structure-activity relationship, kNN- MFA _____________________________________________________________________________________________ INTRODUCTION The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands [1]. The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). Mutations affecting EGFR expression or activity could result in cancer [2]. EGFR exists on the cell surface and is activated by binding of its specific ligands, including epidermal growth factor and transforming growth factor α (TGFα). ErbB2 has no known direct activating ligand, and may be in an activated state constitutively or become active upon heterodimerization with other family members such as EGFR. Upon activation by its growth factor ligands, EGFR undergoes a transition from an inactive monomeric form to an active homodimer [3].In addition to forming homodimers after ligand binding, EGFR may pair with another member of the ErbB receptor family, such as ErbB2/Her2/neu, to create an activated heterodimer. EGFR dimerization stimulates its intrinsic intracellular protein-tyrosine kinase activity. As a result, autophosphorylation of several tyrosine (Y) residues in the C-terminal domain of EGFR occurs. These include Y992, Y1045, Y1068, Y1148 and Y1173 [4]. This autophosphorylation elicits downstream activation and signaling by several other proteins that associate with the phosphorylated tyrosines through their own phosphotyrosine-binding SH2 domains. These downstream signaling proteins initiate several signal transduction cascades, principally the MAPK, Akt and JNK pathways, leading to DNA synthesis and cell proliferation [5]. EGFR overexpression (known as upregulation) or overactivity have been associated with a number of cancers, including head and neck, lung, breast, bladder, prostate, kidney and anal cancers and glioblastoma multiforme. Therefore,