3D-QSAR analysis of benzimidazole inhibitors of interleukin-2 inducible T cell kinase (ITK) considering receptor flexibility and water importance for molecular alignment

作者：Bahia Malkeet Singh; Silakari Om^*

来源：Medicinal Chemistry Research, 2013, 22(11): 5578-5587.

DOI：10.1007/s00044-013-0548-x

• Atom-based 3D-QSAR
• Interleukin-2 inducible T cell kinase (ITK)
• Receptor flexibility
• PHASE
• Rheumatoid arthritis

Interleukin-2 inducible T cell kinase (ITK) plays an essential role in T cell development, differentiation, 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.

• 出版日期2013-11