Active site binding modes of HIV-1 integrase inhibitors

Using the crystal structure of the first complex of the HIV-1 integrase cat alytic core domain with an inhibitor bound to the active site, structural m odels for the interaction of various inhibitors with integrase were generat ed by computational docking. For the compound of the crystallographic study , binding modes unaffected by crystal packing have recently been proposed. Although a large search region was used for the docking simulations, the li gands investigated here are found to bind preferably in similar ways close to the active site. The binding site is formed by residues 64-67, 116, 148, 151-152, 155-156, and 159, as well as by residue 92 in case of the largest ligand of the series. The coherent picture of possible interactions of sma ll-molecule inhibitors at the active site provides an improved basis for st ructure-based ligand design. The recurring motif of tight interaction with the two lysine residues 156 and 159 is suggested to be of prime importance.