Beyond the virtual screening paradigm: structure-based searching for new lead compounds.

The standard approach to structure-based high-throughput virtual screening is a sequential procedure: Each molecule of a given library is screened against the target protein, eventually generating a ranked list of molecules. In this paper a new paradigm avoiding the sequential screening pipeline is presented. Based on a novel descriptor, compounds can be directly accessed by their chemical and shape complementarity to a given protein active site. The docking calculation is performed inherently during the search process since each search result automatically implies a ligand pose in the active site. The new method named TrixX BMI is ideally suited for application scenarios in which medicinal chemists request a certain pharmacophore interaction pattern to a protein. By using an innovative indexing technology, sublinear runtimes in the number of ligands can be achieved. Redocking experiments show that TrixX BMI correctly predicts the pose of the bioactive conformation within an rmsd of less than 2.0 A of the cocrystallized ligand in 80% of 85 protein-ligand complexes of the Astex Diverse Set. In addition to that several comparative enrichment experiments show that TrixX BMI is on a competitive basis to established virtual screening technology, while the observed runtimes are clearly below one second per compound.