Journal of the American Chemical Society
ARTICLE
over 20 for both the WT virus and the Y181C variant. The resul-
tant EC50 values for 36 of 2.5 nM (WT) and 4.9 nM (Y181C) are
striking, given the starting point of the original phenoxy com-
pound 3. In addition, the fold-change (ratio of Y181C to WT
activities) of only a factor of 2 for 36 and its greater potency
toward the Y181C variant than for the reference NNRTIs,
efavirenz and etravirine, are notable. Finally, the potency results
for the methyl analogue 37 are also excellent, with EC50 values of
1.7 and 15 nM toward the WT and mutant viruses, which are
similar to those for efavirenz and etravirine. The CC50 values for
37 are also good, at 2 μM. The improved performance of the 3,5-
disubstituted compounds, 20, 36, and 37, can be attributed to
more complete filling of space in the region spanning between
Cys181, Pro95, and Pro97.
reagents through the NIH AIDS Research and Reference Re-
agent Program, Division of AIDS, NIAID, NIH, is also greatly
appreciated: MT-2 cells, catalog no. 237, and nevirapine-resistant
HIV-1 (N119), catalog no. 1392, from Dr. Douglas Richman;
HTLV-IIIB/H9, no. 398, from Dr. Robert Gallo; and HIV-1IIIB
(A17 variant) from Dr. Emilio Emini.
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’ CONCLUSION
The present study demonstrates the benefit of extensive mole-
cular modeling for efficient discovery of enzyme inhibitors. The
calculations featured structure building with the molecule grow-
ing program BOMB and free energy perturbation calculations for
estimation of relative free energies of binding. The key goal was
to obtain antiviral agents with high potency toward variant forms
of HIV-1 that incorporate the clinically important Tyr181Cys
mutation in HIV reverse transcriptase. With guidance from the
computations, it was possible to progress from the parent
phenoxy-containing 3 with micromolar activity to the extremely
potent analogues 36 and 37 with low-nanomolar potency against
both wild-type HIV-1 and the Tyr181Cys variant. The transfor-
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rings of 3 and for investigating the change of the heterocycle from
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the origins and structureꢀactivity relationships for the T-cell
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turally simple compound 30 is particularly intriguing. Interesting
complexity also arose concerning the preferred conformations of
the new NNRTIs when bound to HIV-RT, as illustrated in
Figures 3 and 7. Ongoing computational and experimental investi-
gations are addressing further these structural questions and
activity toward additional viral variants.
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’ ASSOCIATED CONTENT
S
Supporting Information. Synthetic details; NMR and
b
HRMS spectral data for the compounds in Tables 2 and 4;
complete refs 7 and 11. This material is available free of charge via
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’ AUTHOR INFORMATION
(14) Purstinger, G.; De Palma, A. M.; Zimmerhofer, G.; Huber, S.;
Ladurner, S.; Neyts, J. Bioorg. Med. Chem. Lett. 2008, 18, 5123–5125.
(15) Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 17423–
17429.
Corresponding Author
karen.anderson@yale.edu; william.jorgensen@yale.edu
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’ ACKNOWLEDGMENT
Gratitude is expressed to the National Institutes of Health
(AI44616, GM32136, GM49551) for support and to Dr. Julian
Tirado-Rives for computational assistance. Receipt of the following
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