Docking Validation Resources: Protein Family and Ligand Flexibility Experiments

Abstract

A database consisting of 780 ligand-receptor complexes, termed SB2010, has been derived from the Protein Databank to evaluate the accuracy of docking protocols for regenerating bound ligand conformations. The goal is to provide easily accessible community resources for development of improved procedures to aid virtual screening for ligands with a wide range of flexibilities. Three core experiments using the program DOCK, which employ rigid (RGD), fixed anchor (FAD), and flexible (FLX) protocols, were used to gauge performance by several different metrics: (1) global results, (2) ligand flexibility, (3) protein family, and (4) crossdocking. Global spectrum plots of successes and failures vs rmsd reveal well-defined inflection regions, which suggest the commonly used 2 Å criteria is a reasonable choice for defining success. Across all 780 systems, success tracks with the relative difficulty of the calculations: RGD (82.3%) > FAD (78.1%) > FLX (63.8%). In general, failures due to scoring strongly outweigh those due to sampling. Subsets of SB2010 grouped by ligand flexibility (7-or-less, 8-to-15, and 15-plus rotatable bonds) reveal success degrades linearly for FAD and FLX protocols, in contrast to RGD which remains constant. Despite the challenges associated with FLX anchor orientation and on-the-fly flexible growth, success rates for the 7-or-less (74.5%), and in particular the 8-to-15 (55.2%) subset, are encouraging. Poorer results for the very flexible 15-plus set (39.3%) indicate substantial room for improvement. Family-based success appears largely independent of ligand flexibility suggesting a strong dependence on the binding site environment. For example, zinc-containing proteins are generally problematic despite moderately flexible ligands. Finally, representative crossdocking examples, for carbonic anhydrase, thermolysin, and neuraminidase families, show the utility of family-based analysis for rapid identification of particularly good or bad docking trends, and the type of failures involved (scoring/sampling), which will likely be of interest to researchers making specific receptor choices for virtual screening. SB2010 is available for download at http://rizzolab.org

Fatty Acid-binding Proteins (FABPs) Are Intracellular Carriers for Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD)

“…Likewise, energy grids were generated for the FAAH variants: rat FAAH (PDB code 3QJ8, 2.9-Å resolution), humanized FAAH (PDB code 2WAP, 2.8-Å resolution), and mutant FAAH (a variant created by introducing mutations F160L and M463V in 2WAP with UCSF Chimera v1.9) (22-24). Each ligand molecule was then flexibly docked to each of the respective FABP or FAAH grids (DOCK FLX protocol) (25) and the single lowest energy pose was retained. To generate comparative energy scores, the CBD pose generated in rat FAAH was fixed anchor docked to humanized FAAH and F160L/ M463V mutant FAAH (DOCK FAD protocol) (25) and the single lowest energy pose was retained for each respective FAAH.…”

“…Each ligand molecule was then flexibly docked to each of the respective FABP or FAAH grids (DOCK FLX protocol) (25) and the single lowest energy pose was retained. To generate comparative energy scores, the CBD pose generated in rat FAAH was fixed anchor docked to humanized FAAH and F160L/ M463V mutant FAAH (DOCK FAD protocol) (25) and the single lowest energy pose was retained for each respective FAAH.…”

Destabilization of strigolactone receptor DWARF14 by binding of ligand and E3-ligase signaling effector DWARF3

“…GR24 and SL analog stereoisomers were docked into the D14 LBP using the standard flexible-ligand sampling algorithm [46] implemented in DOCK 6.7 [47]. Ligand placement was prioritized by D-Ring orientation relative to the crystal structure.…”

Thiolactomycin-based β-Ketoacyl-AcpM Synthase A (KasA) Inhibitors

“…Compound 12 is shown in blue. The bound ligand structures were calculated using the DOCK6 suite of dock programs with default parameters (29,31). The substituents occupy the pantetheine-binding pocket consistent with the ILOE data.…”