Glide:  A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy

Abstract

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 search, 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 described Surflex method.

Discovery of Molidustat (BAY 85‐3934): A Small‐Molecule Oral HIF‐Prolyl Hydroxylase (HIF‐PH) Inhibitor for the Treatment of Renal Anemia

“…After protein preparation and ligand extraction, docking studies using Glide SP (Schrödinger LLC)19 were performed, as well as manual docking combined with energy minimizations. BAY‐908 ( 1 ) was docked as the electron‐neutral pyrazolol tautomer.…”

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

“…Virtual docking of αKG was performed using Glide XP (Schrödinger release 2015-3) 53,54 to chain A of the 2.1 Å structure of lactate dehydrogenase A (LDHA pdb identifier: 4OKN 55 ). Missing side chains were automatically constructed, amino acids were assigned protonation states compatible with a pH of 7.0 using the protein preparation wizard (Schrödinger release 2015-3), and crystallographic waters were removed.…”

Biosynthesis and emission of insect-induced methyl salicylate and methyl benzoate from rice

“…A sequence alignment of OsBSMT1 with CbSAMT was performed with Blast (http://www.ncbi.nih.gov/BLAST/) using Blosum62 matrix, followed by the generation of a first model (3D alignment on template) and 200 cycles of molecular dynamics-based simulated annealing. In silico docking of potential substrates was then performed with the Glide program [13], which is part of the SchrödingerÔ suite (Schrödinger, LLC, New York, NY, 2005).…”