Unexpected Isomerisation of a Fragment Analogue During Fragment-Based Screening of HIV Integrase Catalytic Core Domain
John H. Ryan A E , Karen E. Jarvis A , Roger J. Mulder A , Craig L. Francis A , G. Paul Savage A , Olan Dolezal B , Thomas S. Peat B and John J. Deadman C D
+ Author Affiliations
- Author Affiliations
A CSIRO Biomedical Manufacturing Program, Bayview Avenue, Clayton, Vic. 3168, Australia.
B CSIRO Biomedical Manufacturing Program, 343 Royal Parade, Parkville, Vic. 3052, Australia.
C Avexa Pty Ltd, Level 1, 61–63 Camberwell Road, Hawthorn East, Vic. 3123, Australia.
D Current address: Chemocopeia Pty Ltd, 157 Arnold Street, Melbourne, Vic. 3054, Australia.
E Corresponding author. Email: jack.ryan@csiro.au
Australian Journal of Chemistry 68(12) 1871-1879 https://doi.org/10.1071/CH15587
Submitted: 20 September 2015 Accepted: 9 October 2015 Published: 6 November 2015
Abstract
Fragment-based screening of human immunodeficiency virus type 1 (HIV) integrase revealed several aromatic carboxylic acid fragment hits, some of which bound weakly at the site on the HIV-integrase catalytic core domain that binds the lens epithelium-derived growth factor (LEDGF). Virtual screening of an internal database identified an analogue that bound with higher affinity and in an isomerised form to the LEDGF binding site. The starting lactone was stable in CDCl3; however, an unexpected isomerisation process occurred in [D6]DMSO to give the same isomer found in the LEDGF binding site. This hit led directly to a series of low-micromolar LEDGF inhibitors and, via a scaffold hop, to a series of allosteric binding site inhibitors.
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