title: Parallel screening of low molecular weight fragment libraries: do differences in methodology affect hit identification?
abstract: Fragment screening is becoming widely accepted as a technique to identify hit compounds for the development of novel lead compounds. In neighboring laboratories, we have recently, and independently, performed a fragment screening campaign on the HIV-1 integrase core domain (IN) using similar commercially purchased fragment libraries. The two campaigns used different screening methods for the preliminary identification of fragment hits; one used saturation transfer difference nuclear magnetic resonance spectroscopy (STD-NMR), and the other used surface plasmon resonance (SPR) spectroscopy. Both initial screens were followed by X-ray crystallography. Using the STD-NMR/X-ray approach, 15 IN/fragment complexes were identified, whereas the SPR/X-ray approach found 6 complexes. In this article, we compare the approaches that were taken by each group and the results obtained, and we look at what factors could potentially influence the final results. We find that despite using different approaches with little overlap of initial hits, both approaches identified binding sites on IN that provided a basis for fragment-based lead discovery and further lead development. Comparison of hits identified in the two studies highlights a key role for both the conditions under which fragment binding is measured and the criteria selected to classify hits.
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.
authors.forename: Jerome
authors.initials: J
authors.lastname: Wielens
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Headey
authors.forename: David I
authors.initials: DI
authors.lastname: Rhodes
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Mulder
authors.forename: Olan
authors.initials: O
authors.lastname: Dolezal
authors.forename: John J
authors.initials: JJ
authors.lastname: Deadman
authors.forename: Janet
authors.initials: J
authors.lastname: Newman
authors.forename: David K
authors.initials: DK
authors.lastname: Chalmers
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Peat
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Scanlon
mesh_terms: D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D019427:HIV Integrase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries; D020349:Surface Plasmon Resonance / Q000379:methods*
chemical_list: D019428:HIV Integrase Inhibitors; D054852:Small Molecule Libraries; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1