کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1356697 | 981149 | 2008 | 9 صفحه PDF | دانلود رایگان |

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 IC50 values <1 μM 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 (q2 = 0.63, r2 = 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 (IC50avg > 200 μM). 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.
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Journal: Bioorganic & Medicinal Chemistry - Volume 16, Issue 19, 1 October 2008, Pages 8959–8967