Pharmacophore modeling for identification of anti-IGF-1R drugs and in-vitro validation of fulvestrant as a potential inhibitor

PLoS One. 2018 May 22;13(5):e0196312. doi: 10.1371/journal.pone.0196312. eCollection 2018.

Abstract

Insulin-like growth factor 1 receptor (IGF-1R) is an important therapeutic target for breast cancer treatment. The alteration in the IGF-1R associated signaling network due to various genetic and environmental factors leads the system towards metastasis. The pharmacophore modeling and logical approaches have been applied to analyze the behaviour of complex regulatory network involved in breast cancer. A total of 23 inhibitors were selected to generate ligand based pharmacophore using the tool, Molecular Operating Environment (MOE). The best model consisted of three pharmacophore features: aromatic hydrophobic (HyD/Aro), hydrophobic (HyD) and hydrogen bond acceptor (HBA). This model was validated against World drug bank (WDB) database screening to identify 189 hits with the required pharmacophore features and was further screened by using Lipinski positive compounds. Finally, the most effective drug, fulvestrant, was selected. Fulvestrant is a selective estrogen receptor down regulator (SERD). This inhibitor was further studied by using both in-silico and in-vitro approaches that showed the targeted effect of fulvestrant in ER+ MCF-7 cells. Results suggested that fulvestrant has selective cytotoxic effect and a dose dependent response on IRS-1, IGF-1R, PDZK1 and ER-α in MCF-7 cells. PDZK1 can be an important inhibitory target using fulvestrant because it directly regulates IGF-1R.

Publication types

  • Validation Study

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Databases, Pharmaceutical
  • Drug Evaluation, Preclinical
  • Estradiol / analogs & derivatives*
  • Estradiol / chemistry
  • Estradiol / pharmacology
  • Estrogen Receptor Antagonists / chemistry
  • Estrogen Receptor Antagonists / pharmacology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Female
  • Fulvestrant
  • Gene Expression / drug effects
  • Humans
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Ligands
  • MCF-7 Cells
  • Membrane Proteins
  • Models, Chemical
  • Models, Molecular
  • Receptor, IGF Type 1
  • Receptors, Somatomedin / antagonists & inhibitors*
  • Receptors, Somatomedin / chemistry
  • Receptors, Somatomedin / genetics
  • Signal Transduction / drug effects
  • User-Computer Interface

Substances

  • Antineoplastic Agents
  • Carrier Proteins
  • ESR1 protein, human
  • Estrogen Receptor Antagonists
  • Estrogen Receptor alpha
  • IGF1R protein, human
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Ligands
  • Membrane Proteins
  • PDZK1 protein, human
  • Receptors, Somatomedin
  • Fulvestrant
  • Estradiol
  • Receptor, IGF Type 1

Grants and funding

No specific funding was secured to carry out this study.