期刊
CHEMICAL BIOLOGY & DRUG DESIGN
卷 83, 期 2, 页码 141-148出版社
WILEY
DOI: 10.1111/cbdd.12227
关键词
fragment binding; HIV protease; structure-based drug design; X-ray crystallography
资金
- National Institutes of Health [P01 GM083658-05]
- National Institute for General Medical Sciences
- Molecular Basis of Viral Pathogenesis Training Grant [2T32AI007354]
- IBM's World Community Grid
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
- National Center for Research Resources [P41RR001209]
A library of 68 brominated fragments was screened against a new crystal form of inhibited HIV-1 protease in order to probe surface sites in soaking experiments. Often, fragments are weak binders with partial occupancy, resulting in weak, difficult-to-fit electron density. The use of a brominated fragment library addresses this challenge, as bromine can be located unequivocally via anomalous scattering. Data collection was carried out in an automated fashion using AutoDrug at SSRL. Novel hits were identified in the known surface sites: 3-bromo-2,6-dimethoxybenzoic acid (Br6) in the flap site and 1-bromo-2-naphthoic acid (Br27) in the exosite, expanding the chemistry of known fragments for development of higher affinity potential allosteric inhibitors. At the same time, mapping the binding sites of a number of weaker binding Br-fragments provides further insight into the nature of these surface pockets.
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