Docking of Hydroxamic Acids into HDAC1 and HDAC8: A Rationalization of Activity Trends and Selectivities

被引：33

作者：

Ortore, Gabriella ^{[1
]}

Di Colo, Francesco ^{[1
]}

Martinelli, Adriano ^{[1
]}

机构：

[1] Univ Pisa, Dipartimento Sci Farmaceut, I-56126 Pisa, Italy

来源：

JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2009年 / 49卷 / 12期

关键词：

HISTONE DEACETYLASE INHIBITORS; CRYSTAL-STRUCTURE; PANCREATIC-CANCER; GENETIC ALGORITHM; PHASE-I; DESIGN; EXPRESSION; BINDING; DISCOVERY; SUBSTRATE;

D O I：

10.1021/ci900288e

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A docking protocol using Gold software was developed to predict the binding disposition of histone deacetylase (HDAC) inhibitors, starting from the X-ray structures of HDAC8. The optimized procedure was subsequently utilized to dock into HDAC8 and into a homology model of HDAC I nearly 40 compounds that had been tested for their inhibitory activity against the two HDAC isozymes. Evaluation of the best binding poses allowed LIS to identify the ligand properties and the protein residues important for activity and selectivity. HDACs are important anticancer drug targets, and their Study is currently being actively pursued. As such, our results could help design new isozyme-selective HDAC inhibitors. Furthermore, this strategy may also be used for the investigation of other HDACs.

引用

页码：2774 / 2785

页数：12

共 61 条

[1] Gapped BLAST and PSI-BLAST: a new generation of protein database search programs
Altschul, SF
Madden, TL
Schaffer, AA
Zhang, JH
Zhang, Z
Miller, W
Lipman, DJ
[J]. NUCLEIC ACIDS RESEARCH, 1997, 25 (17) : 3389 - 3402
[2] The Protein Data Bank
Berman, HM
Westbrook, J
Feng, Z
Gilliland, G
Bhat, TN
Weissig, H
Shindyalov, IN
Bourne, PE
[J]. NUCLEIC ACIDS RESEARCH, 2000, 28 (01) : 235 - 242
[3] The use of diversity profiling to characterize chemical modulators of the histone deacetylases
Blackwell, Leonard
Norris, Jacqueline
Suto, Carla M.
Janzen, William P.
[J]. LIFE SCIENCES, 2008, 82 (21-22) : 1050 - 1058
[4] Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain
Bottomley, Matthew J.
Lo Surdo, Paola
Di Giovine, Paolo
Cirillo, Agostino
Scarpelli, Rita
Ferrigno, Federica
Jones, Philip
Neddermann, Petra
De Francesco, Raffaele
Steinkuhler, Christian
Gallinari, Paola
Carfi, Andrea
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (39) : 26694 - 26704
[5] Inherent Stereospecificity in the Reaction of Aflatoxin B1 8,9-Epoxide with Deoxyguanosine and Efficiency of DNA Catalysis
Brown, Kyle L.
Bren, Urban
Stone, Michael P.
Guengerich, F. Peter
[J]. CHEMICAL RESEARCH IN TOXICOLOGY, 2009, 22 (05) : 913 - 917
[6] Buggy J. J., 2007, Indole Derivatives as Inhibitors of Histone Deacetylase, Patent No. [WO2007/109178, 2007109178]
[7] Deng W., 2006, PCT Int. Appl., Patent No. [2006101456, WO2006101456A1]
[8] Structural Studies of Human Histone Deacetylase 8 and Its Site-Specific Variants Complexed with Substrate and Inhibitors
Dowling, Daniel P.
Gantt, Stephanie L.
Gattis, Samuel G.
Fierke, Carol A.
Christianson, David W.
[J]. BIOCHEMISTRY, 2008, 47 (51) : 13554 - 13563
[9] The inv(16) fusion protein associates with corepressors via a smooth muscle myosin heavy-chain domain
Durst, KL
Lutterbach, B
Kummalue, T
Friedman, AD
Hiebert, SW
[J]. MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (02) : 607 - 619
[10] Structural origin of selectivity in class II-selective histone deacetylase inhibitors
Estiu, Guillermina
Greenberg, Edward
Harrison, Christopher B.
Kwiatkowski, Nicholas P.
Mazitschek, Ralph
Bradner, James E.
Wiest, Olaf
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (10) : 2898 - 2906

← 1 2 3 4 5 6 7 →