7upj
HIV-1 PROTEASE/U101935 COMPLEX
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| , resolution 2.0Å | |||||||
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| Ligands: | |||||||
| Activity: | HIV-1 retropepsin, with EC number 3.4.23.16 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
OverviewOverview
Recently, cyclooctylpyranone derivatives with m-carboxamide substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a number of these derivatives, which are readily available via a seven-step synthesis. A few of the most potent compounds were further evaluated for such characteristics as pharmacokinetics and toxicity in rats and dogs. From this work, the p-cyanophenyl sulfonamide derivative 35k emerged as a promising inhibitor, was selected for further development, and entered phase I clinical trials.
About this StructureAbout this Structure
7UPJ is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
ReferenceReference
Structure-based design of nonpeptidic HIV protease inhibitors: the sulfonamide-substituted cyclooctylpyramones., Skulnick HI, Johnson PD, Aristoff PA, Morris JK, Lovasz KD, Howe WJ, Watenpaugh KD, Janakiraman MN, Anderson DJ, Reischer RJ, Schwartz TM, Banitt LS, Tomich PK, Lynn JC, Horng MM, Chong KT, Hinshaw RR, Dolak LA, Seest EP, Schwende FJ, Rush BD, Howard GM, Toth LN, Wilkinson KR, Romines KR, et al., J Med Chem. 1997 Mar 28;40(7):1149-64. PMID:9089336
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