Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP
Yan Jia1, Ting-Lan Chiu, Elizabeth A Amin
1Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
Abstract:
Aberrant regulation of cap-dependent translation has been frequently observed in the development of cancer. Association of the cap-binding protein eIF4E with N(7)-methylated guanosine capped mRNA is the rate limiting step governing translation initiation; and therefore represents an attractive process for cancer drug discovery. Previously, replacement of the 7-Me group of the Me(7)-guanosine monophosphate with a benzyl group has been found to increase binding affinity to eIF4E. Recent X-ray crystallographic studies have revealed that the cap-binding pocket undergoes a unique structural change in order to accommodate the benzyl group. To explore the structure-activity relationships governing the affinity of N(7)-benzylated guanosine monophosphate (Bn(7)-GMP) for eIF4E, we virtually screened a library of 80 Bn(7)-GMP analogs utilizing CombiGlide as implemented in Schrodinger. A subset library of substituted Bn(7)-GMP analogs was synthesized and their dissociation constants (K(d)) were determined. Due to the poor correlation between docking/scoring results and experimental binding affinities, three-dimensional quantitative structure-activity relationship (3D-QSAR) calculations were performed. Two highly predictive and self-consistent CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) models were derived and optimized. These models may be useful for the future design of eIF4E cap-binding antagonists.
Insights
Researchers explored N(7)-benzylated guanosine monophosphate (Bn(7)-GMP) analogs to inhibit cancer-related translation initiation. Optimized 3D-QSAR models (CoMFA and CoMSIA) predict binding affinity for designing novel eIF4E cap-binding antagonists.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Aberrant cap-dependent translation is a hallmark of cancer.
- The cap-binding protein eIF4E plays a crucial role in translation initiation, making it a target for cancer drug discovery.
- N(7)-benzylated guanosine monophosphate (Bn(7)-GMP) analogs show increased binding affinity to eIF4E.
Purpose of the Study:
- To investigate the structure-activity relationships of Bn(7)-GMP analogs for eIF4E binding.
- To develop predictive models for designing potent eIF4E cap-binding antagonists.
Main Methods:
- Virtual screening of 80 Bn(7)-GMP analogs using CombiGlide.
- Synthesis and experimental determination of dissociation constants (K(d)) for a subset of analogs.
- Development of 3D-QSAR models (CoMFA and CoMSIA) due to poor correlation between docking and experimental data.
Main Results:
- Two highly predictive and self-consistent CoMFA and CoMSIA models were successfully derived.
- These models establish quantitative structure-activity relationships for Bn(7)-GMP analogs binding to eIF4E.
- The models demonstrated improved predictive power compared to initial docking/scoring results.
Conclusions:
- The developed 3D-QSAR models provide a valuable framework for the rational design of novel eIF4E inhibitors.
- These findings contribute to the development of targeted cancer therapies by modulating translation initiation.
- Further optimization based on these models could lead to potent anti-cancer drug candidates.
