Using three-dimensional substructure searching to identify novel, non-peptidic inhibitors of HIV-1 protease

The design of non-peptidic inhibitors of the human immunodeficiency virus type 1 (HIV-1) protease as potential therapeutic agents against AIDS has been the subject of intense research. Recently, the X-ray crystal structures of several HIV-1 protease/inhibitor complexes have been solved, including one that contains a C₂ symmetric inhibitor, A-74704. In this report, three-dimensional substructure searching, using the program ALADDIN, was used to identify novel, non-peptidic inhibitors of HIV-1 protease. Three-dimensional substructures, or patterns of atoms related by specific geometric constraints, were constructed based on an evaluation of the detailed interactions between A-74704 and the active site of the protease. The substructures included a functional replacement for the buried water molecule observed in the inhibitor/protease complex. Search targets based on these substructures were used to query several large databases of three-dimensional structures to identify small molecule structures with the potential to inhibit HIV-1 protease. Approximately thirty compounds were selected from those found in the searches and tested for HIV-1 protease inhibition. Three structurally-related non-peptidic compounds displayed inhibition in the 10 to 100 μM range. The identification of these compounds may represent an advance towards the de novo design of non-peptidic inhibitors of HIV-1 protease.