2. Academic Validation
  3. Design, Synthesis, and Bioevaluation of Novel MyD88 Inhibitor c17 against Acute Lung Injury Derived from the Virtual Screen

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

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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