Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this way, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystallized PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 A in nearly half of the cases and are greater than 2 A in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently discovered Surflex method.
Glide HTVS can dock compounds at a rate of about 2 seconds/compound and trades sampling breath for higher speeds.
Glide SP performs exhaustive sampling and is the recommended balance between speed and accuracy, requiring about 10 seconds/compound.
Glide XP employs an anchor-and-grow sampling approach and a different functional form for GlideScore. It can dock compounds at a rate of about 2 minutes/compound. These three docking modes provide an array of options in the balance of speed vs. accuracy for most situations.
GlideScore is an empirical scoring function designed to maximize separation of compounds with strong binding affinity from those with little to no binding ability.
Glide offers the full range of speed vs. accuracy options, from the HTVS (high-throughput virtual screening) mode for efficiently enriching million compound libraries, to the SP (standard precision) mode for reliably docking tens to hundreds of thousands of ligand with high accuracy, to the XP (extra precision) mode where further elimination of false positives is accomplished by more extensive sampling and advanced scoring, resulting in even higher enrichment.
Glide provides a rational workflow for virtual screening from HTVS to SP to XP, enriching the data at every level such that only an order of magnitude fewer compounds need to be studied at the next higher accuracy level.
Accurate binding mode prediction:
Glide reliably finds the correct binding modes for a large set of test cases. It outperforms other docking programs in achieving lower RMS deviations from native co-crystallized structures.
Glide exhibits excellent docking accuracy and high enrichment across a diverse range of receptor types.