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Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling.

AbstractAIM:
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.
CONCLUSION:
Three compounds with new structural scaffolds have been identified, which have stronger binding affinities for AKR1B10 than known inhibitors.
AuthorsRaj Kumar, Minky Son, Rohit Bavi, Yuno Lee, Chanin Park, Venkatesh Arulalapperumal, Guang Ping Cao, Hyong-ha Kim, Jung-keun Suh, Yong-seong Kim, Yong Jung Kwon, Keun Woo Lee
JournalActa pharmacologica Sinica (Acta Pharmacol Sin) Vol. 36 Issue 8 Pg. 998-1012 (Aug 2015) ISSN: 1745-7254 [Electronic] United States
PMID26051108 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Biomarkers, Tumor
  • Small Molecule Libraries
  • AKR1B10 protein, human
  • Aldo-Keto Reductases
  • Aldehyde Reductase
Topics
  • Aldehyde Reductase (antagonists & inhibitors, metabolism)
  • Aldo-Keto Reductases
  • Biomarkers, Tumor (antagonists & inhibitors, metabolism)
  • Drug Design
  • Humans
  • Models, Molecular
  • Quantitative Structure-Activity Relationship
  • Small Molecule Libraries (chemistry, pharmacology)
  • Thermodynamics

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