title: Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling.
abstract: OBJECTIVE
  Recent evidence suggests that aldo-keto reductase family 1 B10 (AKR1B10) may be a potential diagnostic or prognostic marker of human tumors, and that AKR1B10 inhibitors offer a promising choice for treatment of many types of human cancers. The aim of this study was to identify novel chemical scaffolds of AKR1B10 inhibitors using in silico approaches.
  
  
  METHODS
  The 3D QSAR pharmacophore models were generated using HypoGen. A validated pharmacophore model was selected for virtual screening of 4 chemical databases. The best mapped compounds were assessed for their drug-like properties. The binding orientations of the resulting compounds were predicted by molecular docking. Density functional theory calculations were carried out using B3LYP. The stability of the protein-ligand complexes and the final binding modes of the hit compounds were analyzed using 10 ns molecular dynamics (MD) simulations.
  
  
  RESULTS
  The best pharmacophore model (Hypo 1) showed the highest correlation coefficient (0.979), lowest total cost (102.89) and least RMSD value (0.59). Hypo 1 consisted of one hydrogen-bond acceptor, one hydrogen-bond donor, one ring aromatic and one hydrophobic feature. This model was validated by Fischer's randomization and 40 test set compounds. Virtual screening of chemical databases and the docking studies resulted in 30 representative compounds. Frontier orbital analysis confirmed that only 3 compounds had sufficiently low energy band gaps. MD simulations revealed the binding modes of the 3 hit compounds: all of them showed a large number of hydrogen bonds and hydrophobic interactions with the active site and specificity pocket residues of AKR1B10.
  
  
  CONCLUSIONS
  Three compounds with new structural scaffolds have been identified, which have stronger binding affinities for AKR1B10 than known inhibitors.
authors.affiliation: 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 (GNU), 501 Jinju-daero, Jinju, 660-701 Republic of Korea.
authors.forename: Raj
authors.initials: R
authors.lastname: Kumar
authors.affiliation: 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 (GNU), 501 Jinju-daero, Jinju, 660-701 Republic of Korea.
authors.forename: Minky
authors.initials: M
authors.lastname: Son
authors.affiliation: 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 (GNU), 501 Jinju-daero, Jinju, 660-701 Republic of Korea.
authors.forename: Rohit
authors.initials: R
authors.lastname: Bavi
authors.affiliation: 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 (GNU), 501 Jinju-daero, Jinju, 660-701 Republic of Korea.
authors.forename: Yuno
authors.initials: Y
authors.lastname: Lee
authors.affiliation: 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 (GNU), 501 Jinju-daero, Jinju, 660-701 Republic of Korea.
authors.forename: Chanin
authors.initials: C
authors.lastname: Park
authors.affiliation: 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 (GNU), 501 Jinju-daero, Jinju, 660-701 Republic of Korea.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Arulalapperumal
authors.affiliation: 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 (GNU), 501 Jinju-daero, Jinju, 660-701 Republic of Korea.
authors.forename: Guang Ping
authors.initials: GP
authors.lastname: Cao
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 Science Education, Kyungnam University, Masan 631-701, Republic of Korea.
authors.forename: Yong-seong
authors.initials: YS
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 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 (GNU), 501 Jinju-daero, Jinju, 660-701 Republic of Korea.
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000074408:Aldo-Keto Reductases; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D014408:Biomarkers, Tumor; D054852:Small Molecule Libraries; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase