4k4q Citations

Crystallographic Fragment Based Drug Discovery: Use of a Brominated Fragment Library Targeting HIV Protease.

Chem Biol Drug Des (2013)
Related entries: 4k4r, 4k4p

Cited: 9 times
EuropePMC logo PMID: 23998903


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. This article is protected by copyright. All rights reserved.

Reviews citing this publication (3)

  1. Successful generation of structural information for fragment-based drug discovery. Öster L, Tapani S, Xue Y, Käck H. Drug Discov. Today 20 1104-1111 (2015)
  2. Fragment-based approaches to anti-HIV drug discovery: state of the art and future opportunities. Huang B, Kang D, Zhan P, Liu X. Expert Opin Drug Discov 10 1271-1281 (2015)
  3. Advantages of crystallographic fragment screening: functional and mechanistic insights from a powerful platform for efficient drug discovery. Patel D, Bauman JD, Arnold E. Prog. Biophys. Mol. Biol. 116 92-100 (2014)

Articles citing this publication (6)

  1. Distinguishing binders from false positives by free energy calculations: fragment screening against the flap site of HIV protease. Deng N, Forli S, He P, Perryman A, Wickstrom L, Vijayan RS, Tiefenbrunn T, Stout D, Gallicchio E, Olson AJ, Levy RM. J Phys Chem B 119 976-988 (2015)
  2. Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection. Sullivan K, Cramer-Morales K, McElroy DL, Ostrov DA, Haas K, Childers W, Hromas R, Skorski T. PLoS ONE 11 e0147230 (2016)
  3. Halogen-enriched fragment libraries as chemical probes for harnessing halogen bonding in fragment-based lead discovery. Zimmermann MO, Lange A, Wilcken R, Cieslik MB, Exner TE, Joerger AC, Koch P, Boeckler FM. Future Med Chem 6 617-639 (2014)
  4. Recovery of the wild type atomic flexibility in the HIV-1 protease double mutants. De Conto V, Braz AS, Perahia D, Scott LP. J. Mol. Graph. Model. 59 107-116 (2015)
  5. Structures of endothiapepsin-fragment complexes from crystallographic fragment screening using a novel, diverse and affordable 96-compound fragment library. Huschmann FU, Linnik J, Sparta K, Ühlein M, Wang X, Metz A, Schiebel J, Heine A, Klebe G, Weiss MS, Mueller U. Acta Crystallogr F Struct Biol Commun 72 346-355 (2016)
  6. Contemporary Use of Anomalous Diffraction in Biomolecular Structure Analysis. Liu Q, Hendrickson WA. Methods Mol. Biol. 1607 377-399 (2017)