Three dimensional pharmacophore modeling of human CYP17 inhibitors. Potential agents for prostate cancer therapy

J Med Chem. 2003 Jun 5;46(12):2345-51. doi: 10.1021/jm020576u.


We report here a molecular modeling investigation of steroidal and nonsteroidal inhibitors of human cytochrome P450 17alpha-hydroxylase-17,20-lyase (CYP17). Using the pharmacophore perception technique, we have generated common-feature pharmacophore model(s) to explain the putative binding requirements for two classes of human CYP17 inhibitors. Common chemical features in the steroid and nonsteroid human CYP17 enzyme inhibitors, as deduced by the Catalyst/HipHop program, are one to two hydrogen bond acceptors (HBAs) and three hydrophobic groups. For azole-steroidal ligands, the 3beta-OH group of ring A and the N-3 of the azole ring attached to ring D at C-17 act as hydrogen bond acceptors. A model that permits hydrogen bond interaction between the azole functionality on ring D and the enzyme is consistent with experimental deductions for type II CYP17 inhibitors where a sixth ligating atom interacts with Fe(II) of heme. In general, pharmacophore models derived for steroid and nonsteroidal compounds bear striking similarities to all azole sites mapping the HBA functionality and to three hydrophobic features describing the hydrophobic interactions between the ligands and the enzyme. Using the pharmacophore model derived for azole-steroidal inhibitors as a 3D search query against several 3D multiconformational Catalyst formatted databases, we identified several steroidal compounds with potential inhibition of this enzyme. Biological testing of some of these compounds show low to high inhibitory potency against the human CYP17 enzyme. This shows the potential of our pharmacophore model in identifying new and potent CYP17 inhibitors. Further refinement of the model is in progress with a view to identifying and optimizing new leads.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Algorithms
  • Antineoplastic Agents / chemistry*
  • Azoles / chemistry
  • Binding Sites
  • Enzyme Inhibitors / chemistry*
  • Humans
  • Hydrogen Bonding
  • Male
  • Models, Molecular
  • Prostatic Neoplasms / drug therapy
  • Protein Binding
  • Quantitative Structure-Activity Relationship
  • Steroid 17-alpha-Hydroxylase / antagonists & inhibitors*
  • Steroids / chemistry*


  • Antineoplastic Agents
  • Azoles
  • Enzyme Inhibitors
  • Steroids
  • Steroid 17-alpha-Hydroxylase