title: QSAR modeling to design selective histone deacetylase 8 (HDAC8) inhibitors.
abstract: HDAC8 inhibitors have become an attractive treatment for cancer. This study aimed to facilitate the identification of potential chemical scaffolds for the selective inhibition of histone deacetylase 8 (HDAC8) using in silico approaches. Non-linear QSAR classification and regression models of HDAC8 inhibitors were developed with support vector machine. Mean impact value-based sequential forward feature selection and grid search strategy were used for molecular descriptor selection and parameter optimization, respectively. The generated QSAR models were validated by leave-one-out cross validation and an external test set. The best QSAR classification model yielded 84 % of accuracy on the external test prediction and Matthews correlation coefficient is 0.69. The best QSAR regression model showed low root-mean-square error (0.63) and high squared correlation coefficient (0.53) for the test set. The validated QSAR models together with various drug-like properties, molecular docking and molecular dynamics simulation were sequentially used as a multi-step query in chemical database virtual screening. Finally, two hit compounds were discovered as new structural scaffolds which can be used for further in vitro and in vivo activity analyses. The strategy used in this study could be a promising computational strategy which can be utilized for other target drug design.
authors.affiliation: Department of Biochemistry, Division of Applied Life Science (BK21 Plus Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Guang Ping
authors.initials: GP
authors.lastname: Cao
authors.affiliation: Department of Biochemistry, Division of Applied Life Science (BK21 Plus Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Sundarapandian
authors.initials: S
authors.lastname: Thangapandian
authors.affiliation: Department of Biochemistry, Division of Applied Life Science (BK21 Plus Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Minky
authors.initials: M
authors.lastname: Son
authors.affiliation: Department of Biochemistry, Division of Applied Life Science (BK21 Plus Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Raj
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Seafood Science and Technology, The Institute of Marine Industry, Gyeongsang National University, Tongyeong, 650-160, Republic of Korea.
authors.forename: Yeung-Joon
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Science Education, Kyungnam University, Masan, 631-701, Republic of Korea.
authors.forename: Yongseong
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Chemical Engineering, Kangwon National University, Chunchon, 200-701, Republic of Korea.
authors.forename: Yong Jung
authors.initials: YJ
authors.lastname: Kwon
authors.affiliation: Division of Quality of Life, Korea Research Institute of Standards and Science, Daejeon, 305-340, Republic of Korea.
authors.forename: Hyong-Ha
authors.initials: HH
authors.lastname: Kim
authors.affiliation: Bio Computing Major, Korean German Institute of Technology, Seoul, 157-033, Republic of Korea.
authors.forename: Jung-Keun
authors.initials: JK
authors.lastname: Suh
authors.affiliation: Department of Biochemistry, Division of Applied Life Science (BK21 Plus Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University, Jinju, Republic of Korea. kwlee@gnu.ac.kr.
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D016208:Databases, Factual; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D021281:Quantitative Structure-Activity Relationship; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases
keywords: Histone deacetylases 8; Molecular docking; Molecular dynamics simulation; QSAR; Support vector machine; Virtual screening