Design, Synthesis, and Bioevaluation of Novel MyD88 Inhibitor c17 against Acute Lung Injury Derived from the Virtual Screen

  • J Med Chem. 2023 May 25;66(10):6938-6958. doi: 10.1021/acs.jmedchem.3c00359.
Pan Chen  1  2  3  4 ,  Ying Zhou  1  4 ,  Xiaobo Li  1  4 ,  Jun Yang  1  4 ,  Zhiwei Zheng  1  3  4 ,  Yu Zou  1  4 ,  Xiang Li  1  4 ,  Jing Liao  1  4 ,  Jintian Dai  4 ,  Yuye Xu  4 ,  Lina Yin  2 ,  Gaozhi Chen  1 ,  Jing Gu  5 ,  Qin Ouyang  5 ,  Won-Jea Cho  3 ,  Qidong Tang  1  4 ,  Guang Liang  1  2  4
Affiliations
  • 1. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
  • 2. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 310053, China.
  • 3. College of Pharmacy, Chonnam National University, Gwangju 61186, Korea.
  • 4. Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China.
  • 5. Department of Medicinal Chemistry, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
PMID: 37130331 DOI: 10.1021/acs.jmedchem.3c00359
Abstract

Myeloid differentiation primary response protein 88 (MyD88) is crucial to immune cascades mediated by Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 dysregulation has been linked to a wide variety of inflammatory diseases, making it a promising new target for anti-inflammatory and Cancer therapy development. In this study, 46 compounds were designed and synthesized inspired by virtual screen hit. The anti-inflammatory activity of designed compounds was evaluated biologically, and c17 was discovered to have a high binding affinity with MyD88. It inhibited the interaction of TLR4 and MyD88 and suppressed the NF-κB pathway. In addition, c17 treatment led to the accumulation in the lungs of rats and attenuated LPS-induced ALI mice model. Furthermore, c17 showed negligible toxicity in vivo. Together, these findings suggest that c17 may serve as a potential therapeutical method for the treatment of ALI and as a lead structure for the continued development of MyD88 inhibitors.

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