Docking-enabled pharmacophore model for histone deacetylase 8 inhibitors and its application in anti-cancer drug discovery.
Zinc-dependent histone deacetylase 8 removes the epsilon-acetyl groups present in the N-terminal lysine residues of histone proteins, thereby restricting various transcription factors from being expressed. Inhibition of this enzyme has been reported to be a novel strategy in cancer treatment. To identify novel and diverse leads for use in potent histone deacetylase 8 inhibitor design, a pharmacophore model showing high correlation between experimental and estimated activities was generated using the best conformations of training set compounds from molecular docking experiments. The best pharmacophore model was validated using four different strategies and then used in database screening for novel virtual leads. Hit compounds were selected and subjected to molecular docking using GOLD. The top-scored compound was further optimized for improved binding. The optimization step led to a new set of compounds with both improved binding at the active site and estimated activities. The identified virtual leads could be used for designing potent histone deacetylase 8 inhibitors as anti-cancer therapeutics.
Thangapandian
Sundarapandian
S
Division of Applied Life Science (BK21 Program), Environmental Biotechnology National Core Research Center (EB-NCRC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU), 900 Gazwa-dong, Jinju 660-701, Republic of Korea.
Sundarapandian
Thangapandian
T
John
Shalini
S
Shalini
John
J
Sakkiah
Sugunadevi
S
Sugunadevi
Sakkiah
S
Lee
Keun Woo
KW
Woo
Lee Keun
LK
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D006655:Histone Deacetylases; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D011487:Protein Conformation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases