Batin Rahaman S K, Nandi Sandip K, Mandal Sudip Kumar, Debnath Utsab
Department of Pharmaceutical Science, School of Health Science and Technology, UPES, Dehradun, Uttarakhand, India.
Department of Chemistry, BITS Pilani K. K. Birla Goa Campus, Goa, India.
Drug Dev Res. 2025 Feb;86(1):e70031. doi: 10.1002/ddr.70031.
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.
Toll样受体4（TLR4）是一种重要的介质，通过其信号通路激活细菌炎症。它在髓样分化蛋白2（MD2）存在的情况下与脂多糖（LPS）结合，使TLR4-MD2-LPS复合物二聚化。TLR4介导的信号通路刺激人类细胞因子的产生，引发炎症反应。TLR4通路的过度激活会触发LPS与TLR4-MD2复合物的结合，这可能导致几种炎症性疾病的发生。因此，TLR4-MD2复合物是鉴定新型有效抗炎药物的潜在治疗靶点。人们探索了各种具有生物活性的靶向TLR4和MD2的天然和合成分子，它们在微摩尔范围内具有抗炎活性。但截至目前，市场上尚无FDA批准的药物，一些药物因耐药性和严重副作用而在临床试验中被停用。在这篇综述中，我们评估了TLR4-MD2拮抗剂的最新分子进展，这些拮抗剂在低微摩尔和纳摩尔水平上表现出直接抑制作用。与此同时，本文还讨论了野生型和突变型TLR4-MD2蛋白结合口袋的蛋白质信息学分析，以深入了解配体结合区域理化性质的变化。我们还指出了TLR4-MD2复合物大LPS结合口袋三个不同位点的几个重要残基，以了解小分子抑制剂（SMIs）的可能结合亲和力。此外，还综述了TLR4拮抗剂的临床试验现状。当前的评估将为设计不同的小分子作为TLR4-MD2复合物的直接抑制剂用于抗炎活性奠定未来的基础。
