Virtual screening of chemical libraries

Abstract

Virtual screening uses computer-based methods to discover new ligands on the basis of biological structures. Although widely heralded in the 1970s and 1980s, the technique has since struggled to meet its initial promise, and drug discovery remains dominated by empirical screening. Recent successes in predicting new ligands and their receptor-bound structures, and better rates of ligand discovery compared to empirical screening, have re-ignited interest in virtual screening, which is now widely used in drug discovery, albeit on a more limited scale than empirical screening.

Figure 1

Complexes predicted from virtual screening compared to X-ray crystallographic structures that were subsequently determined. a, Predicted (carbons in grey) and experimental (green) structures for Sustiva in HIV reverse transcriptase. b, Predicted (magenta) and experimental (carbons in grey) structures of 2,3,4-trimethylthizole in the W191G cavity of cytochrome c peroxidase. c, Predicted (green) and experimental structure (carbons in grey) of an amprenavir mimic in HIV protease (ligands with thick bonds, enzyme residues with thin bonds; structure determined by A. Wlodawer, A. Olson, personal communication).

Figure 2

Virtual screening for new ligands. Large libraries of available, often purchasable, compounds are docked into the structure of receptor targets by a docking computer program. Each compound is sampled in thousands to millions of possible configurations and scored on the basis of its complementarity to the receptor. Of the hundreds of thousands of molecules in the library, tens of top-scoring predicted ligands (hits) are subsequently tested for activity in an experimental assay.

Figure 3

Comparing the structures of new ligands predicted from virtual screening to the structures subsequently determined experimentally. a, The docked (carbons in orange) versus the crystallographic structure (carbons in grey) of the 8.3 μM inhibitor 4-aminophthalhydrazide bound to transfer RNA guanine transglycosylase (ligand in the centre surrounded by enzyme residues). b, The docked (carbons in cyan) versus the crystallographic structure (carbons in grey) of the 100 μM ligand phenol bound to a cavity site in T4 lysozyme (ligand in the centre surrounded by the molecular surface of the surrounding protein residues). c, The docked (carbons in green) versus the crystallographic structure (carbons in red) of the 26 μM inhibitor 3-((4-chloroanilino)-sulphonyl)-thiophene-2-carboxylate bound to AmpC β-lactamase (enzyme carbons in grey). d, The docked (carbons in magenta), re-scored (carbons in cyan) and crystallographic (carbons in grey) structures of a 0.25 μM inhibitor bound to carbonic anhydrase (enzyme carbons in grey). Oxygen atoms in red, sulphurs in yellow, nitrogens in blue. e, The docked (ligand carbons in grey) versus the crystallographic structure (ligand carbons in orange) for a new inhibitor of aldose reductase (enzyme carbons in green). Electron density maps for the ligand are shown in blue. The ordered water (red sphere) observed in the experimental structure was not considered in the docking (H. Steuber and G. Klebe, unpublished work). f, The docked (carbons in cyan) versus the crystallographic structure (carbons in yellow) of the new inhibitor of TEM-1 β-lactamase (enzyme in magenta). The experimentally observed binding mode — 16 Å from the active site targeted in the docking calculations — occurs in a cryptic site absent from the native structure.