Docking performance of the glide program as evaluated on the Astex and DUD datasets: a complete set of glide SP results and selected results for a new scoring function integrating WaterMap and glide

Repasky, Matthew P.; Murphy, Ryan O.; Banks, Jay L.; Greenwood, Jeremy R.; Tubert‐Brohman, Ivan; Bhat, Sathesh; Friesner, Richard A.

doi:10.1007/s10822-012-9575-9

Cited by 133 publications

(140 citation statements)

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“…Inhomogeneous solvation theory has been enthusiastically greeted as a way to model the role of bound water molecules in ligand discovery (25,27,28,31), and has been widely incorporated into discovery methods (34)(35)(36)(37). Despite its successes (4,26,27,29), the method has not been tested in prospective, controlled discovery screens at atomic resolution.…”

Section: Discussionmentioning

confidence: 99%

“…IST has been used to calculate ligand structure-activity relationships (26)(27)(28)(29), map protein binding sites for solvent energetics (28,30,31), quantify the energetic contribution of structural waters (25,32), and understand water networks and how they rearrange in the presence of ligands (33). There have been several implementations of IST, including WaterMap (26,27,31) and STOW (32), and the approach has been integrated into library docking programs such as Glide (34,35), DOCK3.5.54 (36), and AutoDock (37).…”

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confidence: 99%

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Testing inhomogeneous solvation theory in structure-based ligand discovery

Balius

Fischer

Stein

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Binding-site water is often displaced upon ligand recognition, but is commonly neglected in structure-based ligand discovery. Inhomogeneous solvation theory (IST) has become popular for treating this effect, but it has not been tested in controlled experiments at atomic resolution. To do so, we turned to a grid-based version of this method, GIST, readily implemented in molecular docking. Whereas the term only improves docking modestly in retrospective ligand enrichment, it could be added without disrupting performance. We thus turned to prospective docking of large libraries to investigate GIST's impact on ligand discovery, geometry, and water structure in a model cavity site well-suited to exploring these terms. Although top-ranked docked molecules with and without the GIST term often overlapped, many ligands were meaningfully prioritized or deprioritized; some of these were selected for testing. Experimentally, 13/14 molecules prioritized by GIST did bind, whereas none of the molecules that it deprioritized were observed to bind. Nine crystal complexes were determined. In six, the ligand geometry corresponded to that predicted by GIST, for one of these the pose without the GIST term was wrong, and three crystallographic poses differed from both predictions. Notably, in one structure, an ordered water molecule with a high GIST displacement penalty was observed to stay in place. Inclusion of this water-displacement term can substantially improve the hit rates and ligand geometries from docking screens, although the magnitude of its effects can be small and its impact in drug binding sites merits further controlled studies.water | inhomogeneous solvation theory | ligand discovery | structure-based drug design | docking T he treatment of receptor-bound water molecules, which are crucial for ligand recognition, is a widely recognized challenge in structure-based discovery (1-4). The more tightly bound a water in a site, the greater the penalty for its displacement upon ligand binding, ultimately leading to its retention and the adoption of ligand geometries that do not displace it. More problematic still is when a new bridging water mediates interactions between the ligand and the receptor. Because the energetics of bound water molecules have been challenging to calculate and bridging waters hard to anticipate, large-scale docking of chemical libraries has typically been conducted against artificially desolvated sites or has kept a handful of ordered water molecules that are treated as part of the site, based on structural precedence (5-8).Recently, several relatively fast approaches, pragmatic for early discovery, have been advanced to account for the differential displacement energies of bound water molecules (9-20), complementing more rigorous but computationally expensive approaches (18)(19)(20)(21)(22). Among the most popular of these has been inhomogeneous solvation theory (IST) (23)(24)(25). IST uses populations from molecular dynamics (MD) simulations on protein (solute) surfaces to calculate the cost of di...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Testing inhomogeneous solvation theory in structure-based ligand discovery

Balius

Fischer

Stein

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…This, in turn, reflects well-known problems with docking scoring and sampling, the improvement of which remains an area of active research. 42−44 When fragments had poor affinities, as with 5 , or mediocre scores, as with 20 , or both, as with 41 , there was poor correspondence between the docking and crystallographic poses. There was better correspondence between the docking and crystallographic poses of the docking-derived fragments, reflecting both their selection on the basis of highly favorable docking scores, and their affinities, which were typically higher than those of the NMR-derived hits.…”

Section: Discussionmentioning

confidence: 99%

Increasing Chemical Space Coverage by Combining Empirical and Computational Fragment Screens

et al. 2014

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Most libraries for fragment-based drug discovery are restricted to 1,000–10,000 compounds, but over 500,000 fragments are commercially available and potentially accessible by virtual screening. Whether this larger set would increase chemotype coverage, and whether a computational screen can pragmatically prioritize them, is debated. To investigate this question, a 1281-fragment library was screened by nuclear magnetic resonance (NMR) against AmpC β-lactamase, and hits were confirmed by surface plasmon resonance (SPR). Nine hits with novel chemotypes were confirmed biochemically with KI values from 0.2 to low mM. We also computationally docked 290,000 purchasable fragments with chemotypes unrepresented in the empirical library, finding 10 that had KI values from 0.03 to low mM. Though less novel than those discovered by NMR, the docking-derived fragments filled chemotype holes from the empirical library. Crystal structures of nine of the fragments in complex with AmpC β-lactamase revealed new binding sites and explained the relatively high affinity of the docking-derived fragments. The existence of chemotype holes is likely a general feature of fragment libraries, as calculation suggests that to represent the fragment substructures of even known biogenic molecules would demand a library of minimally over 32,000 fragments. Combining computational and empirical fragment screens enables the discovery of unexpected chemotypes, here by the NMR screen, while capturing chemotypes missing from the empirical library and tailored to the target, with little extra cost in resources.

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“…We used Schrödinger's Glide for force field based docking for comparison. In particular, SP 21 and XP 22 modes were used separately. Glide uses grid scoring and hierarchical filtering to select the best scoring poses.…”

Section: Methodsmentioning

confidence: 99%

Importance of Accurate Charges in Binding Affinity Calculations: A Case of Neuraminidase Series

Park¹,

Sung²,

Cho³

2013

Bulletin of the Korean Chemical Society

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It has been shown that calculating atomic charges using quantum mechanical level theory greatly improves the accuracy of docking. A protocol was developed and shown to be effective. That this protocol works is just a manifestation of the fact that electrostatic interactions are important in protein-ligand binding. In order to investigate how the same protocol helps in prediction of binding affinities, we took a series of known cocrystal structures of influenza neuraminidase inhibitors with the receptor and performed docking with Glide SP, Glide XP, and QPLD, the last being a workflow that incorporates QM/MM calculations to replace the fixed atomic charges of force fields with quantum mechanically recalculated ones at a given docking pose, and predicted the binding affinities of each cocrystal. The correlation with experimental binding affinities considerably improved with QPLD compared to Glide SP/XP yielding r 2 = 0.83. The results suggest that for binding sites, such as that of neuraminidase, which are laden with hydrophilic residues, protocols such as QPLD which utilizes QM-based atomic charges can better predict the binding affinities.

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Docking performance of the glide program as evaluated on the Astex and DUD datasets: a complete set of glide SP results and selected results for a new scoring function integrating WaterMap and glide

Cited by 133 publications

References 24 publications

Testing inhomogeneous solvation theory in structure-based ligand discovery

Testing inhomogeneous solvation theory in structure-based ligand discovery

Increasing Chemical Space Coverage by Combining Empirical and Computational Fragment Screens

Importance of Accurate Charges in Binding Affinity Calculations: A Case of Neuraminidase Series

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