Discovery of a Novel MyD88 Inhibitor M20 and Its Protection Against Sepsis-Mediated Acute Lung Injury.

Jiali Song,Yuepiao Cai,Ximing Xu,Xueqin Shi,Qian Liu,Daoxing Chen,Gaozhi Chen,Xiaoyao Lu,Yingqiao Pan

doi:10.3389/fphar.2021.775117

Abstract

Myeloid differentiation factor 88 (MyD88) is a hub protein in the Toll-like receptor signaling pathway, which acts as a master switch for numerous inflammatory diseases, including acute lung injury (ALI). Although this protein is considered as a crucial therapeutic target, there are currently no clinically approved MyD88-targeting drugs. Based on previous literature, here we report the discovery via computer-aided drug design (CADD) of a small molecule, M20, which functions as a novel MyD88 inhibitor to efficiently relieve lipopolysaccharide-induced inflammation both in vitro and in vivo. Computational chemistry, surface plasmon resonance detection (SPR) and biological experiments demonstrated that M20 forms an important interaction with the MyD88-Toll/interleukin-1 receptor domain and thereby inhibits the protein dimerization. Taken together, this study found a MyD88 inhibitor, M20, with a novel skeleton, which provides a crucial understanding in the development and modification of MyD88 inhibitors. Meanwhile, the favorable bioactivity of the hit compound is also conducive to the treatment of acute lung injury or other more inflammatory diseases.

Highlights

Acute lung injury (ALI) is a serious lung disease that is clinically defined as moderate or mild acute respiratory distress syndrome (ARDS)
Many of the previous Myeloid differentiation factor 88 (MyD88) inhibitors were designed based on BB-loop peptidomimetics
To capture the MyD88-Toll/interleukin-1 receptor (TIR) flexible region, in MD simulations, the protein was placed at the temperatures of 300, 330, and 370 K for 50 ns each

Summary

Introduction

Acute lung injury (ALI) is a serious lung disease that is clinically defined as moderate or mild acute respiratory distress syndrome (ARDS). It is caused by various direct or indirect injuries of the lung parenchyma and has an approximately 40% fatality rate (Ding et al, 2020). The leading cause (6–42%) of ALI (Kumar, 2020), is classically activated by lipopolysaccharide (LPS) from Gramnegative pathogens (Dickson and Lehmann, 2019). It is widely known that LPS triggers inflammatory responses by activating Toll-like receptors (TLRs) (Chen et al, 2019). In the TLR signaling pathway, most of the inflammatory responses are mediated by a vital switch molecule called

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Conclusion