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HIV-1 PROTEASE DIMER COMPLEXED WITH A-98881HIV-1 PROTEASE DIMER COMPLEXED WITH A-98881
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe design, synthesis, and molecular modeling studies of a novel series of azacyclic ureas, which are inhibitors of human immunodeficiency virus type 1 (HIV-1) protease that incorporate different ligands for the S1', S2, and S2' substrate-binding sites of HIV-1 protease are described. The synthesis of this series is highly flexible in the sense that the P1', P2, and P2' residues of the inhibitors can be changed independently. Molecular modeling studies on the phenyl ring of the P2 and P2' ligand suggested incorporation of hydrogen-bonding donor/acceptor groups at the 3' and 4-positions of the phenyl ring should increase binding potency. This led to the discovery of compound 7f (A-98881), which possesses high potency in the HIV-1 protease inhibition assay and the in vitro MT-4 cell culture assay (Ki = approximately 5 pM and EC50 = 0.002 microM). This compares well with the symmetrical cyclic urea 1 pioneered at DuPont Merck. A novel, picomolar inhibitor of human immunodeficiency virus type 1 protease.,Sham HL, Zhao C, Stewart KD, Betebenner DA, Lin S, Park CH, Kong XP, Rosenbrook W Jr, Herrin T, Madigan D, Vasavanonda S, Lyons N, Molla A, Saldivar A, Marsh KC, McDonald E, Wideburg NE, Denissen JF, Robins T, Kempf DJ, Plattner JJ, Norbeck DW J Med Chem. 1996 Jan 19;39(2):392-7. PMID:8558507[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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