A 3D QSAR model of 17 beta-HSD1 inhibitors based on a Thieno[2,3-d]pyrimidin-4(3H)-one core applying molecular dynamics Simulations and ligand-protein docking

Sampo Karkola*, Annamaria Lilienkampf, Kristiina Wahala

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) enzyme plays a crucial role in female hormanal regulation by catalysing the NADPH-dependent reduction of the less potent estrone E1 into the biologically active estradiol E2. Because 17 beta HSD1 is a key enzyme in E2 biosynthesis, it has emerged as an attractive drug target for inhibitor development. Herein we report the plausible binding modes and a 3D QSAR model of 17 beta-HSD1 inhibitors based on a (di)cycloalkenothienol[2,3-d]pyrimidin-4(3H)-one core. Two generated enzyme complexes with potent inhibitors were subjected to molecular dynamics simulation to mimic the dynamics process of inhibitor binding. A set of 17 beta-HSD1 inhibitors based on the thieno[2,3-d]pyrimidin-4(3H)-one core were docked into the resulting active site, and a CoMFA model employing the most extensive training set to date was generated. The model was validated with an external test set. Active site residues involved in inhibitor binding and CoMFA fields for steric and electrostatic interactions were identified. The model will be used to guide structural modifications of 17 beta-HSD1 inhibitors based on a thienol[2,3-d]pyrimidin-4(3H)-one core in order to improve the biological activity as well as in the design of novel 17 beta-HSD1 inhibitors.

Original languageEnglish
Pages (from-to)461-472
Number of pages12
JournalChemMedChem
Volume3
Issue number3
DOIs
Publication statusPublished - Mar 2008

Keywords

  • 17 beta-HSD1
  • 3D QSAR
  • breast cancer
  • drug design
  • molecular modeling
  • ESTROGENIC 17-BETA-HYDROXYSTEROID DEHYDROGENASE
  • 17BETA-HYDROXY STEROID DEHYDROGENASES
  • HORMONE-DEPENDENT CANCERS
  • HUMAN BREAST-CARCINOMA
  • AROMATASE INHIBITORS
  • 3-DIMENSIONAL MODEL
  • TYPE-1 17-BETA-HYDROXYSTEROID-DEHYDROGENASE
  • FUNGAL 17-BETA-HYDROXYSTEROID-DEHYDROGENASE
  • POTENT INHIBITORS
  • ACTIVE-SITE

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