WScore: A Flexible and Accurate Treatment of Explicit Water Molecules in Ligand–Receptor Docking

Murphy, Ryan O.; Repasky, Matthew P.; Greenwood, Jeremy R.; Tubert‐Brohman, Ivan; Jerome, Steven V.; Annabhimoju, Ramakrishna; Boyles, Nicholas A.; Schmitz, Christopher D.; Abel, Robert; Farid, Ramy; Friesner, Richard A.

doi:10.1021/acs.jmedchem.6b00131

Cited by 82 publications

(107 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%

“…From these studies, several advantages of IST for ligand discovery emerged: The method meaningfully improved the selection of ligands, and was often right for the right reasons, correctly capturing the role of displaceable or implicitly bridging water. Still, and notwithstanding the great advantages of IST seen in other studies (26)(27)(28)(29)34), in controlled prospective discovery, at atomic resolution, its liabilities also emerge.…”

Section: Significancementioning

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%

Section: Significancementioning

confidence: 99%

mentioning

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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“…Calculating the RMSD has been previously criticized, however, it still remains the most frequently used parameter for describing similarity of conformers [16, 33, 55–57]. …”

Section: Resultsmentioning

confidence: 99%

Searching for bioactive conformations of drug-like ligands with current force fields: how good are we?

Gürsoy

Smieško

2017

J Cheminform

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Drug-like ligands obtained from protein–ligand complexes deposited in the Protein Databank were subjected to conformational searching using various force fields and solvation settings. For each ligand, the resulting conformer pool was examined for the presence of the bioactive (crystal pose-like) conformation. Similarity of conformers toward the crystal-pose was quantified as the best achievable root mean squared deviation (RMSD, heavy atoms only). Analyzing the conformer pools generated by various force fields revealed only small differences in the likelihood of finding a crystal pose-like conformation. However, employing different solvents in the conformational search was found to be very important for achieving RMSDs below 1.0 Å. The best statistical values of likelihood were observed with a recently released force field covering a large portion of dihedral angles occurring in drug-like compounds in combination with the water as solvent. In order to enable computational chemists and modelers to efficiently use available software tools, we have additionally performed several focused analyses on ligands, grouped according to descriptors most relevant for the rational drug design.Electronic supplementary materialThe online version of this article (doi:10.1186/s13321-017-0216-0) contains supplementary material, which is available to authorized users.

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“…Methods that have advanced the correct representation of water molecules in proteins include: free energy perturbation methods (Jorgensen & Thomas, 2008), Monte Carlo probability (Parikh & Kellogg, 2014), molecular dynamics of water on the binding site (as implemented by Schrödinger (Kumar & Zhang, 2013;Waszkowycz, Clark & Gancia, 2011)), water displacement as implemented by PLANTS (Korb, Stützle & Exner, 2009), "Attachment" of water molecules to ligands as additional torsions (Lie, Thomsen, Pedersen, Schiøtt & Christensen, 2011), QM/ MM hybrid methods (Xu & Lill, 2013), COSMO solvation, and semi-empirical charges for ligands (Oferkin et al, 2015). Additional methods are "hydrated docking" scripts for Autodock (Forli et al, 2016), protein-centric and ligand centric hydration as implemented by Rossetta (Lemmon & Meiler, 2013), Water docking using Vina (Ross, Morris & Biggin, 2012;Sridhar et al, 2017), WScore (Murphy et al, 2016), and grid inhomogeneous solvation theory applied by Autodock (Uehara & Tanaka, 2016).…”

Section: Water Solvation and Dockingmentioning

confidence: 99%

Acoplamiento Molecular: Avances Recientes y Retos

2018

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Nota: Artículo recibido el 18 de octubre de 2017 y aceptado el 02 de mayo de 2018. ARTÍCULO DE REVISIÓN abstractAutomated molecular docking aims at predicting the possible interactions between two molecules. This method has proven useful in medicinal chemistry and drug discovery providing atomistic insights into molecular recognition. Over the last 20 years methods for molecular docking have been improved, yielding accurate results on pose prediction. Nonetheless, several aspects of molecular docking need revision due to changes in the paradigm of drug discovery. In the present article, we review the principles, techniques, and algorithms for docking with emphasis on protein-ligand docking for drug discovery. We also discuss current approaches to address major challenges of docking.Key Words: chemoinformatics, computer-aided drug design, drug discovery, structure-activity relationships. Acoplamiento Molecular: Avances Recientes y Retos resuMenEl acoplamiento molecular automatizado tiene como objetivo proponer un modelo de unión entre dos moléculas. Este método ha sido útil en química farmacéutica y en el descubrimiento de nuevos fármacos por medio del entendimiento de las fuerzas de interacción involucradas en el reconocimiento molecular. Durante los últimos 20 años se ha modificado extensamente la técnica de acoplamiento molecular dando resultados precisos en la predicción de los modos de unión. Sin embargo, hay algunas áreas que requieren ser mejoradas substancialmente. En este trabajo se revisan principios, técnicas y algoritmos usados en los programas computacionales del acoplamiento molecular con enfoque en la interacción proteína-ligando aplicado al descubrimiento de nuevos fármacos. También se discuten las estrategias dirigidas a solucionar los principales retos de esta técnica computacional.Palabras Clave: descubrimiento de nuevos fármacos, diseño de fármacos asistido por computadora, quimioinformática, relaciones estructura-actividad.

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WScore: A Flexible and Accurate Treatment of Explicit Water Molecules in Ligand–Receptor Docking

Cited by 82 publications

References 57 publications

Testing inhomogeneous solvation theory in structure-based ligand discovery

Testing inhomogeneous solvation theory in structure-based ligand discovery

Searching for bioactive conformations of drug-like ligands with current force fields: how good are we?

Acoplamiento Molecular: Avances Recientes y Retos

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