STRUCTURE OF HOE BAY-793 COMPLEXED TO HUMAN-IMMUNODEFICIENCY-VIRUS (HIV-1) PROTEASE IN 2 DIFFERENT CRYSTAL FORMS - STRUCTURE/FUNCTION RELATIONSHIP AND INFLUENCE OF CRYSTAL PACKING/

Human immunodeficiency virus 1 (HIV-1) protease is a prime target in t he search for drugs to combat the AIDS virus. The enzyme functions as a C-2-symmetric dimer, cleaving the gag and gag-pol viral polyproteins at distinct sites. The possession of a twofold axis passing through t he active site, has led to the design of C-2-symmetrical inhibitors in the form of substrate-based transition-state analogs. One of the most active compounds of this class of inhibitors is HOE/BAY 793, which co ntains a vicinal diol central unit [Budt, K.-H., Hansen, J., Knolle, J ., Meichsner, C., Paessens, A., Ruppert, D. & Stowasser, B. & Winkler, I. (1990) European Patent application EP0428,849; Budt, K.-H., Hansen , J., Knolle, J., Meichsner, C., Ruppert, D., Paessens, A. & Stowasser B. (1993) IXth International Conference on AIDS; Budt, K.-H., Peyman, A., Hansen, J., Knolle, J., Meichsner, C., Paessens, A., Ruppert, D. & Stowasser, B. (1995) Bioorg. Med. Chem. 3, 559-571.] The structure o f this inhibitor bound to HIV-1 protease, in two different crystal for ms, has been solved at 0.24-nm resolution using X-ray crystallography. In both forms, the details of the inhibitor-protease interactions rev ealed an overall asymmetric binding mode, especially between the centr al diol unit and the active-site aspartates. The main binding interact ions comprise several specific H-bonds and hydrophobic contacts, which rationalize many of the characteristics of the structure/activity rel ationship in the class of vicinal diol inhibitors. In a general analys is of the mobility of the flap regions, which cover the active site an d participate directly in binding, using our structures and the HIV pr otease models present in the Brookhaven databank, we found that in mos t structures the flexibility of the flaps is limited by local crystal contacts. However, in one of the structures presented here, no signifi cant crystal contacts to the flap regions were present, and as a resul t the flexibility of the inhibitor bound flaps increased significantly . This suggests that the mobility and conformational flexibility of th e flap residues are important in the functioning of HIV-1 protease, an d must be considered in the future design of drugs against HIV proteas e and in structure-based drug design in general.