TLR4-Targeting Therapeutics: Structural Basis and Computer-Aided Drug Discovery Approaches

Abstract

The integration of computational techniques into drug development has led to a substantial increase in the knowledge of structural, chemical, and biological data. These techniques are useful for handling the big data generated by empirical and clinical studies. Over the last few years, computer-aided drug discovery methods such as virtual screening, pharmacophore modeling, quantitative structure-activity relationship analysis, and molecular docking have been employed by pharmaceutical companies and academic researchers for the development of pharmacologically active drugs. Toll-like receptors (TLRs) play a vital role in various inflammatory, autoimmune, and neurodegenerative disorders such as sepsis, rheumatoid arthritis, inflammatory bowel disease, Alzheimer’s disease, multiple sclerosis, cancer, and systemic lupus erythematosus. TLRs, particularly TLR4, have been identified as potential drug targets for the treatment of these diseases, and several relevant compounds are under preclinical and clinical evaluation. This review covers the reported computational studies and techniques that have provided insights into TLR4-targeting therapeutics. Furthermore, this article provides an overview of the computational methods that can benefit a broad audience in this field and help with the development of novel drugs for TLR-related disorders.

Toll-Like Receptors in Acute Kidney Injury

“…Many drugs targeting TLR4 are currently being evaluated in phase II and III clinical trials in a variety of inflammatory pathologies, such as rheumatoid arthritis, nonalcoholic steatohepatitis, insulin sensitivity as well as Myelodysplastic syndrome [ 242 ]. Some of these TLR4 inhibitors have strong anti-inflammatory effects and prevent cytokine production in these diseases, such as Eritoran, NI-0101, CX-01 and JKB-121 [ 242 ]. This is why TLR4 signaling pathway has received great interest from researchers in the nephrology field.…”

Enzymatic Regulation and Biological Functions of Reactive Cysteine Persulfides and Polysulfides

“…Excessive and dysregulated activation of TLR4 signaling has been associated with the development of various inflammatory diseases, as well as endotoxin shock pathology [ 62 , 63 , 64 ]. A lot of compounds have been tested in animal models to evaluate their capacity to block TLR4-mediated cytokine production, with several compounds undergoing clinical trials [ 62 , 63 , 64 ]. As mentioned above, NAC polysulfides have potent anti-inflammatory effects, and hence, may become a new class of TLR4 antagonists that can be used to treat endotoxin shock.…”

Revisiting Platelets and Toll-Like Receptors (TLRs): At the Interface of Vascular Immunity and Thrombosis

“…In these clinical trials, the aim of administering these TLR therapeutics is to globally dampen TLR signaling within both immune and non-immune cells expressing TLRs. We direct the reader to the following reviews [ 152 , 153 , 154 , 155 ] that provide a more globalized and in-depth view on TLR therapeutics. Although there has been no focus on how these therapeutics affect platelet-TLR signaling specifically, here we discuss some examples that hold promise for potentially dampening platelet responses in this context.…”