5UPJ

HIV-2 PROTEASE/U99283 COMPLEX

Summary for 5UPJ

• Entry DOI: 10.2210/pdb5upj/pdb
• Descriptor: HIV-2 PROTEASE, 5,6,7,8,9,10-HEXAHYDRO-4-HYDROXY-3-(1-PHENYLPROPYL)CYCLOOCTA[B]PYRAN-2-ONE (3 entities in total)
• Functional Keywords: hydrolase, acid protease, hiv-2 protease-inhibitor complex, protein-substrate interaction, aspartyl protease
• Biological source: Human immunodeficiency virus 2
• 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): P04584
• Total number of polymer chains: 2
• Total formula weight: 21737.03

Authors

Watenpaugh, K.D.,Mulichak, A.M.,Finzel, B.C. (deposition date: 1996-12-10, release date: 1997-04-21, Last modification date: 2024-04-03)

Primary citation

Romines, K.R.,Watenpaugh, K.D.,Tomich, P.K.,Howe, W.J.,Morris, J.K.,Lovasz, K.D.,Mulichak, A.M.,Finzel, B.C.,Lynn, J.C.,Horng, M.-M.,Schwende, F.J.,Ruwart, M.J.,Zipp, G.L.,Chong, K.-T.,Dolak, L.A.,Toth, L.N.,Howard, G.M.,Rush, B.D.,Wilkinson, K.F.,Possert, P.L.,Dalga, R.J.,Hinshaw, R.R.
Use of medium-sized cycloalkyl rings to enhance secondary binding: discovery of a new class of human immunodeficiency virus (HIV) protease inhibitors.
J.Med.Chem., 38:1884-1891, 1995

PubMed Abstract: A unique strategy for the enhancement of secondary binding of an inhibitor to an enzyme has been demonstrated in the design of new human immunodeficiency virus (HIV) protease inhibitors. When the planar benzene ring of a 4-hydroxycoumarin lead compound (1a, Ki = 0.800 microM) was replaced with medium-sized (i.e., 7-9), conformationally-flexible, alkyl rings, the enzyme inhibitory activity of the resulting compounds was dramatically improved, and inhibitors with more than 50-fold better binding (e.g., 5d, Ki = 0.015 microM) were obtained. X-ray crystal structures of these inhibitors complexed with HIV protease indicated the cycloalkyl rings were able to fold into the S1' pocket of the enzyme and fill it much more effectively than the rigid benzene ring of the 4-hydroxycoumarin compound. This work has resulted in the identification of a promising lead structure for the design of potent, deliverable HIV protease inhibitors. Compound 5d, a small (MW = 324), nonpeptidic structure, has already shown several advantages over peptidic inhibitors, including high oral bioavailability (91-99%), a relatively long half-life (4.9 h), and ease of synthesis (three steps).

PubMed: 7783120
DOI: 10.1021/jm00011a008

Experimental method

X-RAY DIFFRACTION (2.3 Å)