Discovery of novel TLR4/MD-2 inhibitors: Receptor structure-based virtual screening studies and anti-inflammatory evaluation

Bioorg Chem. 2023 Sep 27:141:106880. doi: 10.1016/j.bioorg.2023.106880.

Tengyue Zhang ¹, Siqi Xing ², Jiyu Du ³, Jucheng Xia ³, Shuanghong Dong ³, Zeng Li ⁴, Zhicheng Liu ⁵, Yang Song ⁶

Affiliations

1 Department of Oncology, Anhui Provincial Cancer Hospital, West Branch of the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230000, China.
2 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230000, China; The Affiliated Suqian First People's Hospital of Nanjing Medical University, SuQian 223800, China.
3 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230000, China.
4 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230000, China. Electronic address: [email protected].
5 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230000, China. Electronic address: [email protected].
6 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230000, China; Department of Pain, The First Affiliated Hospital of Anhui Medical University, Anhui Medical Uiversity, Hefei 230032, China. Electronic address: [email protected].

PMID: 37783098 DOI: 10.1016/j.bioorg.2023.106880

Abstract

In this study, a receptor structure-based virtual screening strategy was constructed using a computer-aided drug design. First, the compounds were filtered based on the Lipinski pentad and adsorption, distribution, metabolism, excretion, and toxicity profiles. Then, receptor structure-based pharmacophore models were constructed and screened. Finally, the in vitro toxicity and anti-inflammatory activities of hit compounds were initially evaluated to investigate their in vitro anti-inflammatory effects and mechanisms of action. The results revealed that hit 94 had the best anti-inflammatory activity and low toxicity while inhibiting the activation of Toll-like Receptor (TLR) 4/myeloid differentiation factor 2 (MD2)-associated signaling pathways of nuclear factor-κB and mitogen-activated protein kinase. In vivo adjuvant arthritis results also revealed that hit 94 ameliorated foot swelling to a greater extent in rats compared with the positive control drug indomethacin. These results suggest that hit 94 can be used as a potential TLR/MD2 inhibitor for inflammatory diseases.

Keywords

Anti-inflammatory; Hit 94; Receptor structure-based virtual screening; TLR4/MD-2 inhibitors.

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