3D-QSAR studies of 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids as AKR1C3 inhibitors: Highlight the importance of molecular docking in conformation generation

Bioorg Med Chem Lett. 2016 Dec 1;26(23):5631-5638. doi: 10.1016/j.bmcl.2016.10.073. Epub 2016 Nov 1.


AKR1C3 is a promising drug target for castration-resistant prostate cancer (CRPC). Here, 3D-QSAR analysis were performed on 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids to correlate their chemical structures with their observed AKR1C3 inhibitory activity. Three structural alignment methods employing various conformers were used to scrutinize the effect of conformation selection on the predictive accuracy of QSAR models. Using docked conformation, the best CoMFA and CoMSIA models were developed and validated with a training set of 61 molecules and a test set of 7 molecules. Detailed analysis of contour maps provided helpful structural insights to rational design of AKR1C3 inhibitors with enhanced potency.

Keywords: 3D-QSAR; AKR1C3 inhibitors; Benzoic acids; Dihydroisoquinoline; Docking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
  • 3-Hydroxysteroid Dehydrogenases / metabolism
  • Aldo-Keto Reductase Family 1 Member C3
  • Benzoates / chemistry*
  • Benzoates / pharmacology*
  • Binding Sites
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydroxyprostaglandin Dehydrogenases / antagonists & inhibitors*
  • Hydroxyprostaglandin Dehydrogenases / metabolism
  • Isoquinolines / chemistry*
  • Isoquinolines / pharmacology*
  • Molecular Conformation
  • Molecular Docking Simulation
  • Quantitative Structure-Activity Relationship


  • 3,4-dihydroisoquinolin-1(2H)-one
  • Benzoates
  • Enzyme Inhibitors
  • Isoquinolines
  • 3-Hydroxysteroid Dehydrogenases
  • Hydroxyprostaglandin Dehydrogenases
  • AKR1C3 protein, human
  • Aldo-Keto Reductase Family 1 Member C3