ORIGINAL RESEARCH 3D-QSAR analysis of benzimidazole inhibitors of interleukin-2 inducible T cell kinase (ITK) considering receptor flexibility and water importance for molecular alignment Malkeet Singh Bahia • Om Silakari Received: 16 November 2012 / Accepted: 16 February 2013 Ó Springer Science+Business Media New York 2013 Abstract Interleukin-2 inducible T cell kinase (ITK) plays an essential role in T cell development, differentia- tion, and production of Th 2 pro-inflammatory cytokines, such as IL-2, IL-4, IL-5, IL-10, IL-13, and IL-17. Since this kinase is an important contributor in Th 2 cell-mediated autoimmune and allergic disease conditions, e.g. psoriasis, atopic dermatitis, and allergic asthma, the potent inhibitors of ITK may serve as potential therapeutic agents for the treatment of these disease conditions. Thus, a set of 176 benzimidazole ITK inhibitors was employed to perform 3D-QSAR analysis considering the importance of water molecules for docking-based molecular alignment. The best 3D-QSAR model was selected on the basis of the highest value of Q 2 test (0.609). The selected model also displayed the highest values of R 2 train (0.973), F (536.2), and the lowest SD (0.163). The contour plots for different properties would provide beneficial guidance for designing new potent congeners. Keywords Atom-based 3D-QSAR  Interleukin-2 inducible T cell kinase (ITK)  Receptor flexibility  PHASE  Rheumatoid arthritis Introduction Interleukin-2 inducible T cell kinase (ITK) is a 72 kDa protein belonging to Tec family of non-receptor protein tyrosine kinases and plays an essential role in development, differentiation, and activation of T cells (Siliciano et al., 1992). It modulates T cell signaling by activating PLCc1 and regulating the extent of Ca 2? flux. ITK is an important contributor in helper T cell (Th 2)-mediated autoimmune and allergic disorders including psoriasis, atopic dermatitis, and allergic asthma (Ferrara et al., 2006; Von Bonin et al., 2011). Experimentally, ITK-deficient mice showed diminished Th 2 responses to Leishmania major. Moreover, CD 4? cells of ITK knockout mice showed impaired Th 2 differentiation in vitro due to defect in Ca 2? pathway (Fowell et al., 1999). Hence, small inhibitor molecules of ITK would be beneficial in the treatment of various disease conditions associated with T cell signaling (Kaur et al., 2012a). A variety of small ITK inhibitors have been reported in literature, e.g., 2-amino-5-(thioaryl)thiazoles (Das et al., 2006a), 2-amino-5-[(thiomethyl)aryl]thiazoles (Das et al., 2006b), 4 or 5-arylpyrazolyl indoles (Velankar et al., 2010), and benzimidazole derivatives (Fig. 1) (Cook et al., 2009; Lo et al., 2008a, b; Moriarty et al., 2008a, b; Snow et al., 2007; Winters et al., 2008). For the present study, benz- imidazole derivatives have been studied, and in these mol- ecules, the amide linkage present at the second position of ring can adopt two modes of interactions with hinge region; however, experimental X-ray crystallographic studies have supported mode B (Fig. 2a, b) (Moriarty et al., 2008b). Earlier, authors have reported a four point pharmaco- phore model for the development of new ITK inhibitors by virtual screening of molecular database. A large number of diverse molecules were used for the development of pharmacophore model in order to elucidate the three Electronic supplementary material The online version of this article (doi:10.1007/s00044-013-0548-x) contains supplementary material, which is available to authorized users. M. S. Bahia  O. Silakari (&) Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, Punjab, India e-mail: omsilakari@rediffmail.com 123 Med Chem Res DOI 10.1007/s00044-013-0548-x MEDICINAL CHEMISTR Y RESEARCH