Crystallographic fragment-based drug discovery: use of a brominated fragment library targeting HIV protease

Chem Biol Drug Des. 2014 Feb;83(2):141-8. doi: 10.1111/cbdd.12227. Epub 2013 Oct 30.


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.

Keywords: HIV protease; X-ray crystallography; fragment binding; structure-based drug design.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Allosteric Regulation
  • Binding Sites
  • Bromine / chemistry*
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • HIV Protease / chemistry*
  • HIV Protease / genetics
  • HIV Protease / metabolism
  • HIV-1 / enzymology*
  • Humans
  • Hydroxybenzoate Ethers / chemistry
  • Molecular Docking Simulation
  • Naphthalenes / chemistry
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism


  • Hydroxybenzoate Ethers
  • Naphthalenes
  • Protease Inhibitors
  • Recombinant Proteins
  • Small Molecule Libraries
  • 2,6-dimethoxybenzoic acid
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1
  • 2-naphthoic acid
  • Bromine