Structural Diversity and Mutational Challenges of Toll-Like Receptor 4 Antagonists as Inflammatory Pathway Blocker.

Abstract

Toll-like receptor 4 (TLR4) is an important mediator that activates bacterial inflammation through its signaling pathway. It binds lipopolysaccharide (LPS) in the presence of myeloid differentiation protein 2 (MD2) to dimerise the TLR4-MD2-LPS complex. The TLR4 mediated signaling pathway stimulates cytokine production in humans, initiating inflammatory responses. Overactivation of the TLR4 pathway can trigger binding of LPS to the TLR4-MD2 complex, which may lead to the development of several inflammatory disorders. Therefore, the TLR4-MD2 complex is a potential therapeutic target for the identification of new and effective anti-inflammatory agents. Various biologically active TLR4 and MD2 targeting natural and synthetic molecules are explored with anti-inflammatory activity in micromolar ranges. But no FDA-approved drugs are available in the market as of now, and some are discontinued in clinical trials due to drug resistance and severe side effects. In this review, we have assessed recent molecular advancements in TLR4-MD2 antagonists which are showing direct inhibition in lower micro and nanomolar levels. Along with it, protein informatics analysis of the binding pockets of wild type and mutated TLR4-MD2 proteins are also discussed here to give a new insight about the changes in physicochemical properties of the ligand binding area. We have also pointed out several important residues in three different sites of the large LPS binding pocket of TLR4-MD2 complex to understand probable binding affinity of small molecule inhibitors (SMIs). In addition, the present status of clinical trials for TLR4 antagonists is also reviewed. The current assessment will pave a future perspective to design different small molecules as a direct inhibitor of TLR4-MD2 complex for anti-inflammatory activities.