title: Identification of novel potent human testis-specific and bromodomain-containing protein (BRDT) inhibitors using crystal structure-based virtual screening.
abstract: Human testis-specific and bromodomain-containing protein (hBRDT) is essential for chromatin remodeling during spermatogenesis and is therefore an attractive target for the discovery of male contraceptive drugs. In this study, pharmacophore modeling was carried out based on the crystal structure of hBRDT in complex with the inhibitor, JQ1. The established pharmacophore model was used as a 3D search query to identify potent hBRDT inhibitors from an in-house chemical database. A molecular docking analysis was carried out to filter the obtained hit compounds. A total of 125 compounds was finally selected based on the ranking order and visual examination. These compounds were further evaluated by a protein-based in vitro assay. Four compounds with new chemical scaffolds were identified to be hBRDT inhibitors. The most active of these compounds, T480, had a half maximal inhibitory concentration (IC50) of 9.02 µM. The detailed analysis of the binding mode of compound T480 provides important information for the further development of novel BRDT inhibitors.
authors.affiliation: Central Laboratory, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, P.R. China.
authors.forename: Nana
authors.initials: N
authors.lastname: Gao
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Haidian, Beijing 100193, P.R. China.
authors.forename: Jixia
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Reproductive Immunology and Pharamacology, National Research Institute for Family Planning, Beijing 100081, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Hou
authors.affiliation: Department of Reproductive Immunology and Pharamacology, National Research Institute for Family Planning, Beijing 100081, P.R. China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Reproductive Immunology and Pharamacology, National Research Institute for Family Planning, Beijing 100081, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Xin
authors.affiliation: Department of Reproductive Immunology and Pharamacology, National Research Institute for Family Planning, Beijing 100081, P.R. China.
authors.forename: Jiedong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Reproductive Immunology and Pharamacology, National Research Institute for Family Planning, Beijing 100081, P.R. China.
authors.forename: Heming
authors.initials: H
authors.lastname: Yu
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Haidian, Beijing 100193, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Reproductive Immunology and Pharamacology, National Research Institute for Family Planning, Beijing 100081, P.R. China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Wang
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000072417:Protein Domains; D014584:User-Computer Interface; D000092468:Bromodomain Containing Proteins
chemical_list: D009687:Nuclear Proteins; C109570:BRDT protein, human; D000092468:Bromodomain Containing Proteins