Computational drug discovery for designing novel hTLR4 antagonist and their biological evaluation as anti inflammatory anti proliferative agent

Abstract

Abstract newlineToll-Like Receptors (TLRs) are Pattern Recognition Receptor (PRR) and centrally involved in the initiation of the innate and adaptive immune responses. TLRs have shown cellular specificity in terms of ligand recognition, expression and cellular localization in different cell types and tissues, and importantly involved in the pathogenesis of multiple chronic inflammatory diseases. At present, 13 different mammalian TLRs including 11 in human (TLR1-TLR11) and 13 in mice (TLR1-TLR13), with some differences at functional level have been identified. Particularly, TLRs 1 to 11 are conserved in both human and mice, but TLR10 is non-functional in mice, while TLR11 is non-functional in human. In humans, TLRs are expressed on a variety of immune and sentinel cells including myeloid dendritic cells (DCs), monocytes, mast cells, and T and B lymphocytes, synovial fibroblast-like cells and epithelial cells.TLRs are known to have their expression over cell surface, exhibits their response towards bacterial, fungal and protozoan antigens, whereas those TLRs have expression in cytoplasm display response towards the viral, microbial, and host nucleic acids. Indeed, TLRs are also profoundly expressed on various types of cancers and associated with cellular response for cell survival. Toll-like receptor 4 (TLR4) is a member of Toll-Like Receptors (TLRs) family that serves as a receptor for bacterial lipopolysaccharide (LPS). TLR4 alone cannot recognize LPS without aid of co-receptor myeloid differentiation factor-2 (MD-2). Binding of LPS with TLR4 forms a LPSand#8722;TLR4and#8722;MD-2 complex and directs downstream signaling for activation of immune response, inflammation and NF-and#954;B activation. Activation of TLR4 signaling is associated with various inflammatory pathophysiological proveniences. Therefore, targeting protein protein interaction (PPIs) in TLR4and#8722;MD-2 complex formation could be an attractive approach for identifying TLR4 inhibitor.The aim of the present study was to explore the publically available chemical compound library in