![]() In these retrospective experiments, Glide SP reproduces crystal complex geometries in 85% of Astex cases with < 2.5 Å RMSD as shown in Figure 4. The datasets, evaluation metrics, and experiments performed were prescribed by conditions of the Docking and Scoring Symposium at the 241 st ACS Meeting in Anaheim. As part of an unbiased comparison of docking methods, we have evaluated Glide SP for binding mode prediction using the Astex 5 set of self-docking tests, and enrichment in a virtual screening context using the DUD dataset 6. A pre-requisite to obtaining the highest-quality docking results is to use protein and ligand structures prepared using best-practices methods by the Protein Preparation Wizard and LigPrep. Glide’s ability to consistently identify hits for lead optimization and guide understanding of the key interactions and desolvation effects impacting protein-ligand binding have helped drive its widespread adoption. 2016) with many references citing its application in drug discovery projects. The first Glide article 1 is the 2 nd most cited paper ever in the Journal of Medicinal Chemistry (as of Feb. Glide Docking Accuracy and Enrichment Performance The identification of a triplet of correlated hydrogen bonds in the ring in a hydrophobically enclosed region, and the three hydrogen bonds to the ligand carbonyl within that ring each significantly contributes to a very favorable GlideScore for this tightly bound complex (∆Gexp = -18.3 kcal/mol). The naphthyl group receives a hydrophobic enclosure packing reward.įigure 3. Boehringer active for 1kv2 bound to human p38 map kinase. Particularly beneficial to binding is the formation of one or more protein-ligand hydrogen bonds within regions of hydrophobic enclosure as illustrated in Figures 2 and 3.įigure 2. In addition to these terms, GlideScore includes terms to account for hydrophobic enclosure 3, which is the displacement of water molecules by a ligand from areas with many proximal lipophilic protein atoms. As an empirical scoring function it is comprised of terms that account for the physics of the binding process including a lipophilic-lipophilic term, hydrogen bond terms, a rotatable bond penalty, and contributions from protein-ligand coulomb-vdW energies. GlideScore is an empirical scoring function designed to maximize separation of compounds with strong binding affinity from those with little to no binding ability. The Emodel scoring function is primarily defined by the protein-ligand coulomb-vdW energy with a small contribution from GlideScore. Glide uses the Emodel 1 scoring function to select between protein-ligand complexes of a given ligand and the GlideScore 2 function to rank-order compounds to separate compounds that bind strongly (actives) from those that don’t (inactives). ![]() These three docking modes provide an array of options in the balance of speed vs. It can dock compounds at a rate of about 2 minutes/compound. Glide XP employs an anchor-and-grow sampling approach and a different functional form for GlideScore. Glide SP performs exhaustive sampling and is the recommended balance between speed and accuracy, requiring about 10 seconds/compound. Glide HTVS can dock compounds at a rate of about 2 seconds/compound and trades sampling breath for higher speeds. This process is referred to as the docking funnel as illustrated in Figure 1.įigure 1. Finally, a small number of poses are minimized within the field of the receptor with full ligand flexibility (post-docking minimization or PDM). ![]() From poses selected by initial screening, the ligand is refined in torsional space in the field of the receptor using OPLS3 4 (Glide SP & XP) or OPLS2005 (GLIDE HTVS) with a distance-dependent dielectric model. Given these ligand conformations, initial screens are deterministically performed over the entire phase space available to the ligand to locate promising ligand poses. Exhaustive enumeration of ligand torsions generates a collection of ligand conformations that are examined during the docking process. The shape and properties of the receptor are represented on a grid by different sets of fields that provide progressively more accurate scoring of the ligand pose. 1-3 Glide HTVS and SP use a series of hierarchical filters to search for possible locations of the ligand in the binding-site region of a receptor. The Glide HTVS, SP and XP docking methodologies have previously been described in detail.
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