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A5, a New Small-Molecule Inhibitor of CD4 D1 Obtained from a Computer-Aided Screening Method, Contributes to the Inhibition of CD4⁺ T-cell Function

Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China, Department of Pathophysiology, Institute of Radiation Medicine, Beijing, China, Department of Molecular Drug Design, Institute of Pharmacology and Toxicology Sciences, Beijing, China

Jian-Nan Feng

Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China, Department of Pathophysiology, Institute of Radiation Medicine, Beijing, China, Department of Molecular Drug Design, Institute of Pharmacology and Toxicology Sciences, Beijing, China

Zu-Yin Yu

Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China, Department of Pathophysiology, Institute of Radiation Medicine, Beijing, China, Department of Molecular Drug Design, Institute of Pharmacology and Toxicology Sciences, Beijing, China

Lei Zhang

Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China, Department of Pathophysiology, Institute of Radiation Medicine, Beijing, China, Department of Molecular Drug Design, Institute of Pharmacology and Toxicology Sciences, Beijing, China

Ming Yu

Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China, Department of Pathophysiology, Institute of Radiation Medicine, Beijing, China, Department of Molecular Drug Design, Institute of Pharmacology and Toxicology Sciences, Beijing, China

Xin-Hua He

Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China, Department of Pathophysiology, Institute of Radiation Medicine, Beijing, China, Department of Molecular Drug Design, Institute of Pharmacology and Toxicology Sciences, Beijing, China

Song Li

Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China, Department of Pathophysiology, Institute of Radiation Medicine, Beijing, China, Department of Molecular Drug Design, Institute of Pharmacology and Toxicology Sciences, Beijing, China

Bei-Fen Shen

Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China, Department of Pathophysiology, Institute of Radiation Medicine, Beijing, China, Department of Molecular Drug Design, Institute of Pharmacology and Toxicology Sciences, Beijing, China

Yan Li

Department of Molecular Immunology Institute of Basic Medical Sciences Beijing, 100850 China, liyan62033{at}yahoo.com.cn

In this study, the authors apply a computer-based strategy to screen thousands of small-molecule, nonpeptidic organic compounds in the Available Chemicals Directory database and to select a series of potential candidates as ligands of the proposed CD4 D1 surface pocket. Then, several cell-based models are used to determine the actual biological functions of these compounds. A small molecule designated A5 (N-((pyridine-4-yl)methylene)thiophene-2-carbohydrazide) was obtained by a virtual screening followed by 3 cell-based functional assays. The results show that A5 could specifically block the CD4—major histocompatibility complex II binding in a rosetting assay, inhibit the mixed lymphocyte reaction—induced T-cell proliferation in a concentration-dependent manner, and reduce the PMA plus ionomycin—stimulated interleukin-2 secretion from peripheral blood mononuclear cells. (Journal of Biomolecular Screening 2007:800-808)

Key Words: CD4—MHC II interaction • computer-aided screening • novel CD4 D1 inhibitor • cell-based functional assays

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