X-ray Crystallographic Studies of a Series of Penicillin-Derived Asymmetric Inhibitors of HIV-1 Protease

摘要: In the development of a treatment for AIDS, HIV-1 protease has been identified as good target enzyme inhibitor design. We previously reported series dimeric penicillin-derived C2-symmetric inhibitors [Humber, D., et al. (1993) J. Med. Chem. 36, 3120-3128]. an attempt to reduce size and optimize binding these inhibitors, molecular modeling studies led novel monomeric protease. The modes have characterized by X-ray crystallographic NMR studies. Crystal structures complexed three (GR123976, GR126045, GR137615) from this identify details interactions. GR123976 (IC50 = 2.3 microM) exhibits hydrophobic contacts but few electrostatic A strategy structure-based design chemical synthesis elaboration interactions with protein. Crystallographic analysis GR126045 GR137615 catalytic aspartates protein pockets. crystal complexes confirm presence major modeled in order potency reveal recognition nonpeptidic inhibitors.