title: Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP.
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.
authors.affiliation: Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jia
authors.forename: Ting-Lan
authors.initials: TL
authors.lastname: Chiu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Amin
authors.forename: Vitaly
authors.initials: V
authors.lastname: Polunovsky
authors.forename: Peter B
authors.initials: PB
authors.lastname: Bitterman
authors.forename: Carston R
authors.initials: CR
authors.lastname: Wagner
mesh_terms: D000595:Amino Acid Sequence; D002851:Chromatography, High Pressure Liquid; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors*; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D021281:Quantitative Structure-Activity Relationship; D012315:RNA Caps; D012044:Regression Analysis
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D012315:RNA Caps; D006157:Guanosine Monophosphate