title: Identification of alternative binding sites for inhibitors of HIV-1 ribonuclease H through comparative analysis of virtual enrichment studies.
abstract: The ribonuclease H (RNase H) domain on the p66 monomer of HIV-1 reverse transcriptase enzyme has become a target for inhibition. The active site is one potential binding site, but other RNase H sites can accommodate inhibitors. Using a combination of experimental and computational studies, potential new binding sites and binding modes have been identified. Libraries of compounds were screened with an experimental assay to identify actives without knowledge of the binding site. The compounds were computationally docked at putative binding sites. Based on positive enrichment of natural-product actives relative to the database of compounds, we propose that many inhibitors bind to an alternative, potentially allosteric, site centered on Q507 of p66. For a series of hydrazone compounds, a small amount of positive enrichment was obtained when active compounds were bound by induced-fit docking at the interface between the DNA:RNA substrate and the RNase H domain near residue Q500.
authors.affiliation: BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, New Jersey 08854, USA. felts@lutece.rutgers.edu
authors.forename: Anthony K
authors.initials: AK
authors.lastname: Felts
authors.forename: Krystal
authors.initials: K
authors.lastname: Labarge
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Bauman
authors.forename: Dishaben V
authors.initials: DV
authors.lastname: Patel
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Himmel
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
authors.forename: Michael A
authors.initials: MA
authors.lastname: Parniak
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Levy
mesh_terms: D000495:Allosteric Site / Q000187:drug effects; D001665:Binding Sites; D020134:Catalytic Domain / Q000187:drug effects; D003198:Computer Simulation; D005973:Glutamine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000737:chemistry / Q000201:enzymology; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006835:Hydrazones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012372:ROC Curve; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D016914:Ribonuclease H / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries
chemical_list: D006834:Hydrazines; D006835:Hydrazones; D018894:Reverse Transcriptase Inhibitors; D054852:Small Molecule Libraries; D005973:Glutamine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H