7UPJ

HIV-1 PROTEASE/U101935 COMPLEX

Summary for 7UPJ

• Entry DOI: 10.2210/pdb7upj/pdb
• Descriptor: HIV-1 PROTEASE, N-(3-CYCLOPROPYL(5,6,7,8,9,10-HEXAHYDRO-2-OXO-2H-CYCLOOCTA[B]PYRAN-3-YL)METHYL)PHENYLBENZENSULFONAMIDE (3 entities in total)
• Functional Keywords: hydrolase, acid protease, aspartyl protease
• Biological source: Human immunodeficiency virus 1
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03367
• Total number of polymer chains: 2
• Total formula weight: 22087.10

Authors

Watenpaugh, K.D.,Janakiraman, M.N. (deposition date: 1996-12-05, release date: 1997-04-21, Last modification date: 2024-04-03)

Primary citation

Skulnick, H.I.,Johnson, P.D.,Aristoff, P.A.,Morris, J.K.,Lovasz, K.D.,Howe, W.J.,Watenpaugh, K.D.,Janakiraman, M.N.,Anderson, D.J.,Reischer, R.J.,Schwartz, T.M.,Banitt, L.S.,Tomich, P.K.,Lynn, J.C.,Horng, M.-M.,Chong, K.-T.,Hinshaw, R.R.,Dolak, L.A.,Seest, E.P.,Schwende, F.J.,Rush, B.D.,Howard, G.M.,Toth, L.N.,Wilkinson, K.F.,Kakuk, T.J.,Johnson, C.W.,Cole, S.L.,Zaya, R.M.,Zipp, G.L.,Possert, P.L.,Dalga, R.J.,Zhong, W.-Z.,Williams, M.G.,Romines, K.R.
Structure-based design of nonpeptidic HIV protease inhibitors: the sulfonamide-substituted cyclooctylpyramones.
J.Med.Chem., 40:1149-1164, 1997

PubMed Abstract: 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.

PubMed: 9089336
DOI: 10.1021/jm960441m

Experimental method

X-RAY DIFFRACTION (2 Å)