Computational identification of novel histone deacetylase inhibitors by docking based QSAR

• Published in: Computers in biology and medicine Vol. 42; no. 6; pp. 697 - 705
• Main Authors: Nair, Syam B, Teli, Mahesh Kumar, Pradeep, H, Rajanikant, G.K
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01-06-2012; Elsevier Limited
• Subjects: 3D–QSAR; Algorithms; Anti-cancer; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Benzimidazole and imidazole inhibitors; Benzimidazoles - chemistry; Benzimidazoles - metabolism; Cancer; Catalytic Domain; Chemistry, Pharmaceutical - methods; Docking; Drug Discovery - methods; Enzymes; HDAC; Histone Deacetylase 2 - antagonists & inhibitors; Histone Deacetylase 2 - chemistry; Histone Deacetylase 2 - metabolism; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - metabolism; Histone Deacetylase Inhibitors - pharmacology; Humans; Imidazoles - chemistry; Imidazoles - metabolism; Internal Medicine; Ligands; Methods; Models, Molecular; Other; Pharmacophore; Quantitative Structure-Activity Relationship; Regression Analysis; Reproducibility of Results; ROC Curve; Studies; Virtual screening; Virtual screening; Docking; Benzimidazole and imidazole inhibitors; Anti-cancer; 3D–QSAR; Pharmacophore; HDAC
• ISSN: 0010-4825; 1879-0534
• DOI: 10.1016/j.compbiomed.2012.04.001

Abstract Histone deacetylases (HDACs) are enzymes that modify chromatin structure and contribute to aberrant gene expression in cancer. A series compounds with well-assigned HDAC inhibitory activity was used for docking based 3D–QSAR analysis. The 3D–QSAR acquired had excellent correlation coefficient value ( q2 =0.753) and high Fisher ratio ( F =300.2). A validated pharmacophore model (AAAPR) was employed for virtual screening. After manual selection, molecular docking and further refinement, six compounds with good absorption, distribution, metabolism, and excretion (ADME) properties were selected as potential HDAC inhibitors. Further, the molecular interactions of these inhibitors with the HDAC active site residues were discussed in detail.