CSAR Data Set Release 2012: Ligands, Affinities, Complexes, and Docking Decoys

Abstract

A major goal in drug design is the improvement of computational methods for docking and scoring. The Community Structure Activity Resource (CSAR) has collected several data sets from industry and added in-house data sets that may be used for this purpose (). CSAR has currently obtained data from Abbott, GlaxoSmithKline, and Vertex and is working on obtaining data from several others. Combined with our in-house projects, we are providing a data set consisting of 6 protein targets, 647 compounds with biological affinities, and 82 crystal structures. Multiple congeneric series are available for several targets with a few representative crystal structures of each of the series. These series generally contain a few inactive compounds, usually not available in the literature, to provide an upper bound to the affinity range. The affinity ranges are typically 3–4 orders of magnitude per series. For our in-house projects, we have had compounds synthesized for biological testing. Affinities were measured by Thermofluor, Octet RED, and isothermal titration calorimetry for the most soluble. This allows the direct comparison of the biological affinities for those compounds, providing a measure of the variance in the experimental affinity. It appears that there can be considerable variance in the absolute value of the affinity, making the prediction of the absolute value ill-defined. However, the relative rankings within the methods are much better, and this fits with the observation that predicting relative ranking is a more tractable problem computationally. For those in-house compounds, we also have measured the following physical properties: logD, logP, thermodynamic solubility, and pKa. This data set also provides a substantial decoy set for each target consisting of diverse conformations covering the entire active site for all of the 58 CSAR-quality crystal structures. The CSAR data sets (CSAR-NRC HiQ and the 2012 release) provide substantial, publically available, curated data sets for use in parametrizing and validating docking and scoring methods.

TACI deficiency enhances antibody avidity and clearance of an intestinal pathogen

“…Bioluminescence imaging (BLI) was run at 25°C with Octet RED (ForteBio) (46)(47)(48). K D was deduced from association and dissociation rates of NP-specific Ig (in dilutions of 0.3-10 nM) and measured with super streptavidin sensors (ForteBio) loaded with biotinylated NP 4 -BSA (Biosearch Technologies).…”

DOCK 6: Impact of new features and current docking performance

“…In addition to direct empirical confirmation, the performances of DOCK and other docking programs are occasionally evaluated in formal docking competitions and special symposia. [29–32] A brief list of widely used docking programs, primarily selected from a survey of published literature from 2010–2011, [33] includes: AutoDock, [34] AutoDock Vina, [35] GOLD, [36,37] Glide, [38,39] Surflex, [40] FlexX, [41] ICM, [42] FRED, [43] MOE, [44] CDOCKER, [45] and eHITS. [46] A detailed summary of the latest developments in these programs and others can be found in a recent review by Yuriev and Ramsland.…”

The SAMPL4 host–guest blind prediction challenge: an overview

“…The Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL) exercise [5–7], as well as other blind prediction efforts including the Community Structure–Activity Resource [4, 8], Critical Assessment of Protein Structure Prediction [9], and the pKa Cooperative [10] have proven the value of blind prediction challenges in evaluating various computational methods widely used for molecular modeling and drug discovery. Although the first SAMPL challenges focused mainly on prediction of solvation free energies and tautomeric states of drug-like small molecules [5, 6, 11, 12], SAMPL’s scope has expanded significantly, through the addition of not only protein–ligand but also host–guest binding affinities, starting with SAMPL3 in 2011 [7, 13] and continuing with the current SAMPL4 exercise [14, 15].…”