Volker Schnecke, Leslie A. Kuhn
Abstract
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.