title: Identification of a novel scaffold for allosteric inhibition of wild type and drug resistant HIV-1 reverse transcriptase by fragment library screening.
abstract: A novel scaffold inhibiting wild type and drug resistant variants of human immunodeficiency virus type 1 reverse transcriptase (HIV-1RT) has been identified in a library consisting of 1040 fragments. The  fragments were significantly different from already known non-nucleoside reverse transcriptase inhibitors (NNRTIs), as indicated by a Tversky similarity analysis. A screening strategy involving SPR biosensor-based interaction analysis and enzyme inhibition was used. Primary biosensor-based screening, using short concentration series, was followed by analysis of nevirapine competition and enzyme inhibition, thus identifying inhibitory fragments binding to the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Ten hits were discovered, and their affinities and resistance profiles were evaluated with wild type and three drug resistant enzyme variants (K103N, Y181C, and L100I). One fragment exhibited submillimolar K(D) and IC(50) values against all four tested enzyme variants. A substructure comparison between the fragment and 826 structurally diverse published NNRTIs confirmed that the scaffold was novel. The fragment is a bromoindanone with a ligand efficiency of 0.42 kcal/mol(-1).
authors.affiliation: Beactica AB, Box 567, SE-751 22 Uppsala, Sweden.
authors.forename: Matthis
authors.initials: M
authors.lastname: Geitmann
authors.forename: Malin
authors.initials: M
authors.lastname: Elinder
authors.forename: Christian
authors.initials: C
authors.lastname: Seeger
authors.forename: Peter
authors.initials: P
authors.lastname: Brandt
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: U Helena
authors.initials: UH
authors.lastname: Danielson
mesh_terms: D000494:Allosteric Regulation; D019380:Anti-HIV Agents / Q000737:chemistry*; D001665:Binding Sites; D015374:Biosensing Techniques; D016208:Databases, Factual; D024882:Drug Resistance, Viral; D057075:Enzyme Assays; D054303:HIV Reverse Transcriptase / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology*; D057166:High-Throughput Screening Assays; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase