Details

Autor(en) / Beteiligte

• Hou, Xuben
• Du, Jintong
• Liu, Renshuai
• Zhou, Yi
• Li, Minyong
• Xu, Wenfang
• Fang, Hao

Titel

Enhancing the Sensitivity of Pharmacophore-Based Virtual Screening by Incorporating Customized ZBG Features: A Case Study Using Histone Deacetylase 8

Ist Teil von

• Journal of chemical information and modeling, 2015-04, Vol.55 (4), p.861-871

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.