Abstract
Inhibitor of kappa B kinase subunit β (IKKβ) is a main regulator of nuclear factor kappa B (NF-κB) and has received considerable attention as an attractive therapeutic target for the treatment of lung cancer or other inflammatory disease. A group of diversified thienopyridine derivatives exhibited a wide range of biological activity was used to investigate its structural requirements by using DFT and 3D-Quantitative structure activity relationship. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were established using the experimental activity of thienopyridine derivatives. The cross-validation coefficient (q2) values for CoMFA and CoMSIA are 0.671 and 0.647 respectively, were achieved, demonstrating high predictive capability of the model. The contour analysis indicate that presence of hydrophobic and electrostatic field is highly desirable for biological activity. The results indicate that substitution of hydrophobic group with electron withdrawing effect at R4 and R6 position have more possibility to increase the biological activity of thienopyridine derivatives. Subsequently molecular docking and DFT calculation were performed to assess the potency of the compounds.
Highlights
Nuclear Factor Kappa B (NF-κB), a highly conserved and chief inducible transcription factor that regulates multiple aspects of immune system [1]. It plays a crucial role in coordinating inflammatory responses by regulating the adhesive molecules chemokines, vascular endothelial growth factor (VEGF), interleukin IL-1, interleukin IL-6, cyclooxygenase (COX)-2, matrix metallo proteinases (MMPs), 5-lipooxygenase (5-LOX) and tumor necrosis factor (TNF) [2]
Three Inhibitor of kappa B kinase subunit β (IKKβ) inhibitors EB-1627, EB-1627 and IMD-1041 have been reported in different phases of clinical studies, but due to selectivity issue none of them have approved in phase III [14, 15]
Docking results indicate that the investigated compounds bind to the active site of the kinase domain of IKKβ located at the hinge region connecting C-lobe and N-lobe
Summary
Nuclear Factor Kappa B (NF-κB), a highly conserved and chief inducible transcription factor that regulates multiple aspects of immune system [1]. It plays a crucial role in coordinating inflammatory responses by regulating the adhesive molecules chemokines, vascular endothelial growth factor (VEGF), interleukin IL-1, interleukin IL-6, cyclooxygenase (COX)-2, matrix metallo proteinases (MMPs), 5-lipooxygenase (5-LOX) and tumor necrosis factor (TNF) [2]. The aberrant activation of NF-ĸB signaling results in several diseases, such as sensitivity to infections, cancers and autoimmunity [4, 5, 6]. Drug-discovery efforts have identified several small molecules reported against the IKKs that are selective for IKKβ over IKKα. Three IKKβ inhibitors EB-1627, EB-1627 and IMD-1041 have been reported in different phases of clinical studies, but due to selectivity issue none of them have approved in phase III [14, 15]
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