title: Crystallographic fragment-based drug discovery: use of a brominated fragment library targeting HIV protease.
abstract: 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.
authors.affiliation: Department of Integrative Computational and Structural Biology, TSRI, 10550 N. Torrey Pines Rd., La Jolla, CA, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Tiefenbrunn
authors.forename: Stefano
authors.initials: S
authors.lastname: Forli
authors.forename: Meaghan
authors.initials: M
authors.lastname: Happer
authors.forename: Ana
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Yingssu
authors.initials: Y
authors.lastname: Tsai
authors.forename: Michael
authors.initials: M
authors.lastname: Soltis
authors.forename: John H
authors.initials: JH
authors.lastname: Elder
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Olson
authors.forename: Charles D
authors.initials: CD
authors.lastname: Stout
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D001966:Bromine / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D062425:Hydroxybenzoate Ethers / Q000737:chemistry; D062105:Molecular Docking Simulation; D009281:Naphthalenes / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism
chemical_list: D062425:Hydroxybenzoate Ethers; D009281:Naphthalenes; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; C472445:2,6-dimethoxybenzoic acid; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; C030037:2-naphthoic acid; D001966:Bromine
keywords: HIV protease; X-ray crystallography; fragment binding; structure-based drug design