Optimization and determination of the absolute configuration of a series of potent inhibitors of human papillomavirus type-11 E1–E2 protein–protein interaction: A combined medicinal chemistry, NMR and computational chemistry approach

We have previously reported the discovery and initial SAR optimization of the first series of inhibitors of the human papillomavirus type-11 (HPV11) E1–E2 protein–protein interaction. These inhibitors featured an indandione system spiro-fused onto an all syn substituted tetrahydrofuran ring. In this...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2007-04, Vol.15 (7), p.2690-2700
Main Authors: Goudreau, Nathalie, Cameron, Dale R., Déziel, Robert, Haché, Bruno, Jakalian, Araz, Malenfant, Eric, Naud, Julie, Ogilvie, William W., O’Meara, Jeff, White, Peter W., Yoakim, Christiane
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Antiviral Agents - chemical synthesis
Antiviral Agents - pharmacology
Biological and medical sciences
Chemistry, Pharmaceutical
Chromatography, High Pressure Liquid
Computational Biology
Computer Simulation
DNA-Binding Proteins - antagonists & inhibitors
Epoxy Compounds - chemistry
Human papillomavirus
Human papillomavirus 11 - drug effects
Human papillomavirus 11 - metabolism
Humans
Indandione, NMR
Indicators and Reagents
Magnetic Resonance Spectroscopy
Medical sciences
Models, Molecular
Molecular Conformation
Pharmacology. Drug treatments
Protein–protein interaction
Spectrometry, Mass, Electrospray Ionization
Stereoisomerism
Structure-Activity Relationship
Viral Proteins - antagonists & inhibitors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:We have previously reported the discovery and initial SAR optimization of the first series of inhibitors of the human papillomavirus type-11 (HPV11) E1–E2 protein–protein interaction. These inhibitors featured an indandione system spiro-fused onto an all syn substituted tetrahydrofuran ring. In this paper, we report new SAR efforts which have led to the identification of the first low nanomolar inhibitor of the HPV11 E1–E2 protein–protein interaction. In addition, we report a combined NMR and computational chemistry approach which allowed the successful determination of the absolute stereochemistry of the active species originating from the initial racemic lead.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2007.01.036