1HPO
HIV-1 PROTEASE TRIPLE MUTANT/U103265 COMPLEX
Summary for 1HPO
| Entry DOI | 10.2210/pdb1hpo/pdb |
| Descriptor | HIV-1 PROTEASE, 4-CYANO-N-(3-CYCLOPROPYL(5,6,7,8,9,10-HEXAHYDRO-4-HYDROXY-2-OXO-CYCLOOCTA[B]PYRAN-3-YL)METHYL)PHENYL BENZENSULFONAMIDE (3 entities in total) |
| Functional Keywords | hydrolase, acid protease, aspartyl protease |
| Biological source | Human immunodeficiency virus 1 |
| Cellular location | Gag-Pol polyprotein: Host cell membrane ; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03367 |
| Total number of polymer chains | 2 |
| Total formula weight | 22114.21 |
| Authors | Watenpaugh, K.D.,Janakiraman, M.N. (deposition date: 1996-12-10, release date: 1997-04-21, Last modification date: 2024-02-07) |
| 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.R.,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 Cited by 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: 9089336DOI: 10.1021/jm960441m PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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