Database screening for HIV protease ligands: the influence of binding-site conformation and representation on ligand selectivity.

Screening for potential ligands and docking them into the binding sites of proteins is one of the main tasks in computer-aided drug design. Despite the progress in computational power, it remains infeasible to model all the factors involved in molecular recognition, especially when screening databases of more than 100,000 compounds. While ligand flexibility is considered in most approaches, the model of the binding site is rather simplistic, with neither solvation nor induced complementary usually taken into consideration. We present results for screening different databases for HIV-1 protease ligands with our tool Slide, and investigate the extent to which binding-site conformation, solvation, and template representation generate bias. The results suggest a strategy for selecting the optimal binding-site conformation, for cases in which more than one independent structure is available, and selecting a representation of that binding site that yields reproducible results and the identification of known ligands.