Computational selection of small molecule inhibitors of the eIF4E:eIF4G protein-protein complex involved in cancer
Vajda and Beglov groups
American Cancer Society institutional pilot grant IRG 72 001-36-IRG (PI: D. Beglov)
The objective of this project is to identify novel inhibitors of the translation initiation factor eIF4E by extensive, fast and reliable screening of large virtual libraries of chemical compounds.
EIF4E is a well validated drug target which is misused by cancer cells for survival and propagation. Recently it was predicted that the most potent of the existing inhibitors – 4E1RCat, which inhibits cap-dependent translation with IC50 of 4 µM, binds to the eIF4E site, responsible for binding to a natural inhibitor 4E-BP1 and also to the initiation factor eIF4G. It was shown that the detailed characterization of the eIF4E:eIF4G interface by a method of computational solvent mapping, developed in Structural Bioinformatics Lab, is capable to improve predictive quality of molecular docking and to generate realistic docking poses of existing inhibitors of eIF4E in agreement with the experimental data. We further demonstrated that the computational screening based on the correlation of the docked ligands to the density of molecular probes at the hot spot regions allowed us to select the 3 experimentally validated inhibitors of the translation initiation in the subset of 6 out of 108 prospective molecules.
In order to deal with larger virtual libraries we are currently performing initial fast filtering of multiple conformers of the ligand using an efficient hot spot matching algorithm. The accuracy of screening predictions will be further improved by the incorporation of the information about the probe chemical properties into the density correlation method. We are also using the knowledge of the chemical composition of the existing inhibitors of the eIF4E in our screening selections.
Since all known eIF4E inhibitors are relatively weak binders, we are screening databases of commercially and academically available chemical compounds such as ZINC and BU-CMLD to generate a virtual library of potentially more potent inhibitors.
This pilot project will ignite further research in the area of cancer suppression. Dr. Pelletier (McGill University) is interested in potential results of this project and is willing to test the predicted set of compounds for inhibition of the eIF4E:eIF4G interaction in his laboratory.
EIF4E is overexpressed in various cancer types including prostate, breast, stomach, colon, lung, skin and blood malignancies. Increased expression of eIF4E is associated with the severity of disease. Elevated total eIF4E levels along with 4EBP1 phosphorylation, which increases the availability of eIF4E to bind with eIF4G and enhance cap-dependent translation, has been observed in both breast cancer and prostate cancer and correlates with decreased survival. At the same time only few low micromolar inhibitors of translation initiation are known currently, which makes the screening for new high affinity compounds of primary importance. Disruption of the translational initiation by small molecular inhibitors is a promising strategy to overcome cancer chemoresistance and to improve patient survival.