AutoDock-GIST: Incorporating Thermodynamics of Active-Site Water into Scoring Function for Accurate Protein-Ligand Docking

Uehara, Shota; Tanaka, Shigenori

doi:10.3390/molecules21111604

Cited by 54 publications

(56 citation statements)

References 99 publications

(136 reference statements)

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“…S2, and Table S1). Here, enthalpy was not normalized by occupancy (SI Appendix, section S2), in contrast to previous studies (28,37), but still referenced to bulk water energy, as this produced the best enrichments. Following convention, negative GIST energies reflect favorable, costly-todisplace waters.…”

Section: Resultsmentioning

confidence: 99%

“…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: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…Structure–activity relationships are then explained by displacement of strongly or weakly bound solvent molecules, where displacement of weakly bound solvent is expected to increase binding affinities. This treatment of binding site desolvation can help to improve the accuracy of docking algorithms and lead to enhanced scoring functions …”

Section: Introductionmentioning

confidence: 99%

Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations

Wahl

Smieško

2018

ChemMedChem

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Computational methods, namely molecular dynamics (MD) simulations in combination with inhomogeneous fluid solvation theory (IFST) were used to retrospectively investigate various cases of ligand structure modifications that led to the displacement of binding site water molecules. Our findings are that water displacement per se is energetically unfavorable in the discussed examples, and that it is merely the fine balance between change in protein-ligand interaction energy, ligand solvation free energies, and binding site solvation free energies that determine if water displacement is favorable or not. We furthermore evaluated if we can reproduce experimental binding affinities by a computational approach combining changes in solvation free energies with changes in protein-ligand interaction energies and entropies. In two of the seven cases, this estimation led to large errors, implying that accurate predictions of relative binding free energies based on solvent thermodynamics is challenging. Nevertheless, MD simulations can provide insight regarding which water molecules can be targeted for displacement.

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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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AutoDock-GIST: Incorporating Thermodynamics of Active-Site Water into Scoring Function for Accurate Protein-Ligand Docking

Cited by 54 publications

References 99 publications

Testing inhomogeneous solvation theory in structure-based ligand discovery

Testing inhomogeneous solvation theory in structure-based ligand discovery

Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations

Acoplamiento Molecular: Avances Recientes y Retos

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