title: Native State Mass Spectrometry, Surface Plasmon Resonance, and X-ray Crystallography Correlate Strongly as a Fragment Screening Combination.
abstract: Fragment-based drug discovery (FBDD) is contingent on the development of analytical methods to identify weak protein-fragment noncovalent interactions. Herein we have combined an underutilized fragment screening method, native state mass spectrometry, together with two proven and popular fragment screening methods, surface plasmon resonance and X-ray crystallography, in a fragment screening campaign against human carbonic anhydrase II (CA II). In an initial fragment screen against a 720-member fragment library (the "CSIRO Fragment Library") seven CA II binding fragments, including a selection of nonclassical CA II binding chemotypes, were identified. A further 70 compounds that comprised the initial hit chemotypes were subsequently sourced from the full CSIRO compound collection and screened. The fragment results were extremely well correlated across the three methods. Our findings demonstrate that there is a tremendous opportunity to apply native state mass spectrometry as a complementary fragment screening method to accelerate drug discovery.
authors.affiliation: Griffith University , Eskitis Institute for Drug Discovery, Brisbane, Queensland Australia.
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Woods
authors.affiliation: CSIRO Biomedical Manufacturing Program, Melbourne, Victoria Australia.
authors.forename: Olan
authors.initials: O
authors.lastname: Dolezal
authors.affiliation: CSIRO Biomedical Manufacturing Program, Melbourne, Victoria Australia.
authors.forename: Bin
authors.initials: B
authors.lastname: Ren
authors.affiliation: CSIRO Biomedical Manufacturing Program, Melbourne, Victoria Australia.
authors.forename: John H
authors.initials: JH
authors.lastname: Ryan
authors.affiliation: CSIRO Biomedical Manufacturing Program, Melbourne, Victoria Australia.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Peat
authors.affiliation: Griffith University , Eskitis Institute for Drug Discovery, Brisbane, Queensland Australia.
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Poulsen
mesh_terms: D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D054852:Small Molecule Libraries; D024402:Carbonic Anhydrase II