The crystal structures at 2.2-A resolution of hydroxyethylene-based inhibitors bound to human immunodeficiency virus type 1 protease show that the inhibitors are present in two distinct orientations

As part of a structure-based drug design program directed against enzyme targets in the human immunodeficiency virus (HIV), we have determined the three-dimensional structures of the HIV type 1 protease complexed with two hydroxyethylene-based inhibitors.The inhibitors (SKF 107457 and SKF 108738) are hexapeptide substrate analogues with the scissile bond being replaced by a hydroxyethylene isostere.The structures were determined using x-ray diffraction data to 2.2 A measured at the Cornel1 High Energy Synchrotron Source on hexagonal crystals of each of the complexes.The structures have been extensively refined using a reciprocal space least-squares method to conventional crystallographic R factors of 0.186 and 0.159, respectively.The protein structure differs from that in the unliganded state of the enzyme and is most similar to that of the structure of the other reported (Jaskolski, M., Tomasselli, A.