title: Experimental validation of a fragment library for lead discovery using SPR biosensor technology.
abstract: A new fragment library for lead discovery has been designed and experimentally validated for use in surface plasmon resonance (SPR) biosensor-based screening. The 930 compounds in the library were selected from 4.6 million commercially available compounds using a series of physicochemical and medicinal chemistry filters. They were screened against 3 prototypical drug targets: HIV-1 protease, thrombin and carbonic anhydrase, and a nontarget: human serum albumin. Compound solubility was not a problem under the conditions used for screening. The high sensitivity of the sensor surfaces allowed the detection of interactions for 35% to 97% of the fragments, depending on the target protein. None of the fragments was promiscuous (i.e., interacted with a stoichiometry ≥5:1 with all 4 proteins), and only 2 compounds dissociated slowly from all 4 proteins. The use of several targets proved valuable since several compounds would have been disqualified from the library on the grounds of promiscuity if fewer target proteins had been used. The experimental procedure allowed an efficient evaluation and exploration of the new fragment library and confirmed that the new library is suitable for SPR biosensor-based screening.
authors.affiliation: Department of Biochemistry and Organic Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Elinder
authors.forename: Matthis
authors.initials: M
authors.lastname: Geitmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Gossas
authors.forename: Per
authors.initials: P
authors.lastname: Källblad
authors.forename: Johan
authors.initials: J
authors.lastname: Winquist
authors.forename: Helena
authors.initials: H
authors.lastname: Nordström
authors.forename: Markku
authors.initials: M
authors.lastname: Hämäläinen
authors.forename: U Helena
authors.initials: UH
authors.lastname: Danielson
mesh_terms: D000818:Animals; D015374:Biosensing Techniques / Q000379:methods*; D024402:Carbonic Anhydrase II / Q000378:metabolism; D002417:Cattle; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000378:metabolism; D016333:HIV Protease / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D054852:Small Molecule Libraries; D020349:Surface Plasmon Resonance / Q000379:methods*; D013917:Thrombin / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D012709:Serum Albumin; D054852:Small Molecule Libraries; D013917:Thrombin; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D024402:Carbonic Anhydrase II