title: A Thoroughly Validated Virtual Screening Strategy for Discovery of Novel HDAC3 Inhibitors.
abstract: Histone deacetylase 3 (HDAC3) has been recently identified as a potential target for the treatment of cancer and other diseases, such as chronic inflammation, neurodegenerative diseases, and diabetes. Virtual screening (VS) is currently a routine technique for hit identification, but its success depends on rational development of VS strategies. To facilitate this process, we applied our previously released benchmarking dataset, i.e., MUBD-HDAC3 to the evaluation of structure-based VS (SBVS) and ligand-based VS (LBVS) combinatorial approaches. We have identified FRED (Chemgauss4) docking against a structural model of HDAC3, i.e., SAHA-3 generated by a computationally inexpensive "flexible docking", as the best SBVS approach and a common feature pharmacophore model, i.e., Hypo1 generated by Catalyst/HipHop as the optimal model for LBVS. We then developed a pipeline that was composed of Hypo1, FRED (Chemgauss4), and SAHA-3 sequentially, and demonstrated that it was superior to other combinations in terms of ligand enrichment. In summary, we present the first highly-validated, rationally-designed VS strategy specific to HDAC3 inhibitor discovery. The constructed pipeline is publicly accessible for the scientific community to identify novel HDAC3 inhibitors in a time-efficient and cost-effective way.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. dreaming@imm.ac.cn.
authors.forename: Huabin
authors.initials: H
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. jiexia@imm.ac.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. wangdmchina@imm.ac.cn.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wang
authors.affiliation: Molecular Modeling and Drug Discovery Core for District of Columbia Center for AIDS Research (DC CFAR), Department of Pharmaceutical Sciences, College of Pharmacy, Howard University, Washington, DC 20059, USA. x.simon.wang@gmail.com.
authors.forename: Xiang Simon
authors.initials: XS
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. ws@imm.ac.cn.
authors.forename: Song
authors.initials: S
authors.lastname: Wu
mesh_terms: D019540:Area Under Curve; D002384:Catalysis; D004353:Drug Evaluation, Preclinical; D056572:Histone Deacetylase Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D008024:Ligands; D062105:Molecular Docking Simulation; D012372:ROC Curve; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D014584:User-Computer Interface; D000099186:Histone Deacetylase 3
chemical_list: D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D008024:Ligands; D000099186:Histone Deacetylase 3
keywords: HDAC3 inhibitors; MUBD-HDACs; anti-diabetes; benchmarking calculation; virtual screening