{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T15:39:04Z","timestamp":1715787544543},"reference-count":51,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2004,9,7]],"date-time":"2004-09-07T00:00:00Z","timestamp":1094515200000},"content-version":"vor","delay-in-days":3598,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Comput Chem"],"published-print":{"date-parts":[[1994,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ro 31\u20108959 is a highly potent inhibitor of HIV\u20101 proteinase in phase III clinical trials for treatment of AIDS. It is also the first subnanomolar inhibitor that demonstrated reversed stereochemical preference at the central hydroxyl group. Free energy perturbation calculations have been carried out to rationalize the preference for the R\u2010diastereomer by consideration of two models of the (weaker) S\u2010diastereomer. In the first model, the central hydroxyl group makes only one hydrogen bond with the active site aspartates, whereas the hydroxyl group in the second model makes at least three strong hydrogen bonds. Using the first model, the free energy difference in binding of Ro 31\u20108959 and its S\u2010diastereomer is calculated to be 3.4 kcal\/mol, which is in close agreement with the experimental value. Although the second model has a more favorable interaction with the active site aspartates compared to the first model, it has a higher energy N\u2010axial conformation at the decahydroisoquinoline group in P<jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/tex2gif-stack-1.gif\" xlink:title=\"urn:x-wiley:01928651:media:JCC540151106:tex2gif-stack-1\" \/>. We show here that the two contributions cancel each other and the two models of S\u2010diastereomer are predicted to have equivalent binding. The stereochemical preference in a hydroxyethylamine series of inhibitors appears to be affected by both intermolecular and intramolecular (conformational) energies. The binding data on the proline containing inhibitors are rationalized based on these results. \u00a9 1994 by John Wiley &amp; Sons, Inc.<\/jats:p>","DOI":"10.1002\/jcc.540151106","type":"journal-article","created":{"date-parts":[[2005,1,2]],"date-time":"2005-01-02T00:57:39Z","timestamp":1104627459000},"page":"1241-1253","source":"Crossref","is-referenced-by-count":9,"title":["Reversed stereochemical preference in binding of Ro 31\u20108959 to HIV\u20101 proteinase: A free energy perturbation analysis"],"prefix":"10.1002","volume":"15","author":[{"given":"B. G.","family":"Rao","sequence":"first","affiliation":[]},{"given":"M. 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H. M.","year":"1992","journal-title":"J. Biol. Chem."},{"key":"e_1_2_1_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2686029"},{"key":"e_1_2_1_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00038a001"},{"key":"e_1_2_1_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00112a048"},{"key":"e_1_2_1_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/5.1.29"},{"key":"e_1_2_1_13_2","unstructured":"E. E.Kim B. G.Rao D. D.Deininger R. D.Tung M. D.Dwyer J. A.Thomson S. H.Rotstein J.Boger M. A.Murcko andM. A.Navia Communicated toNature Structural Biology. The diffraction data on the crystal of the HIV\u20101 proteinase\u2010Ro 31\u20108959 complex in P61space group were collected out to 2.3 \u00c5 and refined to an R\u2010value of 0.18."},{"key":"e_1_2_1_14_2","doi-asserted-by":"publisher","DOI":"10.1080\/00268979200101321"},{"key":"e_1_2_1_14_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0959-440X(91)90002-B","volume":"1","author":"McCammon J. A.","year":"1991","journal-title":"Curr. Op. Struct. Biol."},{"key":"e_1_2_1_14_4","doi-asserted-by":"publisher","DOI":"10.1038\/347631a0"},{"key":"e_1_2_1_14_5","doi-asserted-by":"publisher","DOI":"10.1021\/ar00176a002"},{"key":"e_1_2_1_14_6","doi-asserted-by":"publisher","DOI":"10.1021\/ar00161a004"},{"key":"e_1_2_1_14_7","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1146\/annurev.bb.18.060189.002243","volume":"18","author":"Beveridge D. L.","year":"1989","journal-title":"Ann. Rev. Biophys. and Biophys. 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