Computational identification of novel histone deacetylase inhibitors by docking based QSAR

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.

[1]  W. L. Jorgensen,et al.  Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids , 1996 .

[2]  P. Liberator,et al.  Histone deacetylase: a target for antiproliferative and antiprotozoal agents. , 2001, Current medicinal chemistry.

[3]  G. Estiu,et al.  Residues in the 11 A channel of histone deacetylase 1 promote catalytic activity: implications for designing isoform-selective histone deacetylase inhibitors. , 2008, Journal of medicinal chemistry.

[4]  Leming Shi,et al.  Quantitative structure-activity relationship study of histone deacetylase inhibitors. , 2004, Current medicinal chemistry. Anti-cancer agents.

[5]  M. Pazin,et al.  What's Up and Down with Histone Deacetylation and Transcription? , 1997, Cell.

[6]  V. Kulkarni,et al.  Pharmacophore generation and atom-based 3D-QSAR of novel 2-(4-methylsulfonylphenyl)pyrimidines as COX-2 inhibitors , 2010, Molecular Diversity.

[7]  M. Sturlese,et al.  SAR and QSAR study on 2-aminothiazole derivatives, modulators of transcriptional repression in Huntington's disease. , 2008, Bioorganic & medicinal chemistry.

[8]  M. Guenther,et al.  Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen* , 2001, The Journal of Biological Chemistry.

[9]  P. Marks,et al.  Inhibitors of histone deacetylase are potentially effective anticancer agents. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[10]  P. Marks,et al.  Histone deacetylases and cancer: causes and therapies , 2001, Nature Reviews Cancer.

[11]  Matthew P. Repasky,et al.  Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. , 2004, Journal of medicinal chemistry.

[12]  Lingzhou Zhao,et al.  3D-QSAR study of Chk1 kinase inhibitors based on docking , 2010, Journal of Molecular Modeling.

[13]  V. Richon,et al.  Histone deacetylase inhibitors as new cancer drugs , 2001, Current opinion in oncology.

[14]  M. Navre,et al.  Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity. , 2010, Bioorganic & medicinal chemistry letters.

[15]  Minoru Yoshida,et al.  [Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A]. , 1990, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[16]  E. Seto,et al.  Acetylation and deacetylation of non-histone proteins. , 2005, Gene.

[17]  A. V. van Kuilenburg,et al.  Histone deacetylases (HDACs): characterization of the classical HDAC family. , 2003, The Biochemical journal.

[18]  S. Minucci,et al.  Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer , 2006, Nature Reviews Cancer.

[19]  Mahipal,et al.  3D QSAR of aminophenyl benzamide derivatives as histone deacetylase inhibitors. , 2010, Medicinal chemistry (Shariqah (United Arab Emirates)).

[20]  John Eng,et al.  Receiver operating characteristic analysis: a primer. , 2005, Academic radiology.

[21]  Hao Tang,et al.  Novel Inhibitors of Human Histone Deacetylase (HDAC) Identified by QSAR Modeling of Known Inhibitors, Virtual Screening, and Experimental Validation , 2009, J. Chem. Inf. Model..

[22]  L. Di Croce,et al.  HDAC1, a novel marker for benign teratomas , 2010, The EMBO journal.

[23]  David E. Shaw,et al.  PHASE: a new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results , 2006, J. Comput. Aided Mol. Des..

[24]  M. Teli,et al.  Pharmacophore generation and atom-based 3D-QSAR of novel quinoline-3-carbonitrile derivatives as Tpl2 kinase inhibitors , 2012, Journal of enzyme inhibition and medicinal chemistry.

[25]  Woody Sherman,et al.  ConfGen: A Conformational Search Method for Efficient Generation of Bioactive Conformers , 2010, J. Chem. Inf. Model..

[26]  P. Marks,et al.  Histone deacetylase inhibitors: from target to clinical trials , 2002, Expert opinion on investigational drugs.