title: Bisphosphonate inhibitors of ATP-mediated HIV-1 reverse transcriptase catalyzed excision of chain-terminating 3'-azido, 3'-deoxythymidine: a QSAR investigation.
abstract: We report the results of an investigation of the inhibition of the ATP-mediated HIV-1 reverse transcriptase catalyzed phosphorolysis in vitro of AZT from AZT-terminated DNA primers by a series of 42 bisphosphonates. The four most active compounds possess neutral, halogen-substituted phenyl or biphenyl sidechains and have IC(50) values < 1 microM in excision inhibition assays. Use of two comparative molecular similarity analysis methods to analyze these inhibition results yielded a classification model with an overall accuracy of 94%, and a regression model having good accord with experiment (q(2)=0.63, r(2)=0.91), with the experimental activities being predicted within, on average, a factor of 2. The most active species had little or no toxicity against three human cell lines (IC(50)(avg) > 200 microM). These results are of general interest since they suggest that it may be possible to develop potent bisphosphonate-based AZT-excision inhibitors with little cellular toxicity, opening up a new route to restoring AZT sensitivity in otherwise resistant HIV-1 strains.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA.
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
authors.forename: Julian M W
authors.initials: JM
authors.lastname: Chan
authors.forename: Zev
authors.initials: Z
authors.lastname: Tovian
authors.forename: Aaron
authors.initials: A
authors.lastname: Secrest
authors.forename: Eva
authors.initials: E
authors.lastname: Nagy
authors.forename: Kilannin
authors.initials: K
authors.lastname: Krysiak
authors.forename: Kyle
authors.initials: K
authors.lastname: Bergan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Parniak
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000378:metabolism; D054306:Dideoxynucleotides / Q000737:chemistry / Q000378:metabolism*; D004164:Diphosphonates / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006219:Halogens / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D010756:Phosphoric Acids / Q000737:chemistry / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis; D013942:Thymine Nucleotides / Q000737:chemistry / Q000378:metabolism*; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D017931:DNA Primers; D054306:Dideoxynucleotides; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D006219:Halogens; D010756:Phosphoric Acids; D013942:Thymine Nucleotides; C057287:3'-azido-3'-deoxythymidine 5'phosphate; D015215:Zidovudine; D000255:Adenosine Triphosphate; D054303:HIV Reverse Transcriptase
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