title: Enhancing the Sensitivity of Pharmacophore-Based Virtual Screening by Incorporating Customized ZBG Features: A Case Study Using Histone Deacetylase 8.
abstract: As key regulators of epigenetic regulation, human histone deacetylases (HDACs) have been identified as drug targets for the treatment of several cancers. The proper recognition of zinc-binding groups (ZBGs) will help improve the accuracy of virtual screening for novel HDAC inhibitors. Here, we developed a high-specificity ZBG-based pharmacophore model for HDAC8 inhibitors by incorporating customized ZBG features. Subsequently, pharmacophore-based virtual screening led to the discovery of three novel HDAC8 inhibitors with low micromole IC50 values (1.8-1.9 μM). Further studies demonstrated that compound H8-A5 was selective for HDAC8 over HDAC 1/4 and showed antiproliferation activity in MDA-MB-231 cancer cells. Molecular docking and molecular dynamic studies suggested a possible binding mode for H8-A5, which provides a good starting point for the development of HDAC8 inhibitors in cancer treatment.
authors.affiliation: †Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Xuben
authors.initials: X
authors.lastname: Hou
authors.affiliation: ‡Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, China.
authors.forename: Jintong
authors.initials: J
authors.lastname: Du
authors.affiliation: †Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Renshuai
authors.initials: R
authors.lastname: Liu
authors.affiliation: †Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: †Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Minyong
authors.initials: M
authors.lastname: Li
authors.affiliation: †Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Xu
authors.affiliation: †Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Fang
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D011487:Protein Conformation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D014584:User-Computer Interface; D015032:Zinc / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases; D015032:Zinc