Ensemble Docking into Flexible Active Sites. Critical Evaluation of FlexE Against JNK‐3 and β‐Secretase.

Polgár, Tímea; Keserue, G. M.

doi:10.1002/chin.200641219

Cited by 16 publications

(30 citation statements)

References 1 publication

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“…However, consideration of too many conformations can lead to reduced performance. In a recent critical evaluation of FlexE on two targets of pharmaceutical interest, β-secretase and JNK-3, the algorithm was unable to handle large loop movements and could not match enrichment factors obtained by running multiple independent FlexX runs on each receptor structure [13].…”

Section: Ensemble Dockingmentioning

confidence: 99%

Flexible ligand docking to multiple receptor conformations: a practical alternative

Totrov

Abagyan

2008

Current Opinion in Structural Biology

447

386

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State of the art docking algorithms predict an incorrect binding pose for about 50-70% of all ligands when only a single fixed receptor conformation is considered. In many more cases, lack of receptor flexibility results in meaningless ligand binding scores, even when the correct pose is obtained. Incorporating conformational rearrangements of the receptor binding pocket into predictions of both ligand binding pose and binding score is crucial for improving structure-based drug design and virtual ligand screening methodologies. However, direct modeling of protein binding site flexibility remains challenging because of the large conformational space that must be sampled, and difficulties remain in constructing a suitably accurate energy function. Here we show that using multiple fixed receptor conformations, either experimentally determined by crystallography or NMR, or computationally generated, is a practical shortcut that may improve docking calculations. In several cases, such an approach has led to experimentally validated predictions.

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Section: Ensemble Dockingmentioning

confidence: 99%

Flexible ligand docking to multiple receptor conformations: a practical alternative

Totrov

Abagyan

2008

Current Opinion in Structural Biology

447

386

View full text Add to dashboard Cite

show abstract

“…During the enrichment study, 6011 ligands were docked using the FlexE/ScreenScore docking scheme, and the authors found that enrichments in different ensembles could not even reach that yielded by FlexX and stated that the enrichment declined sharply with an increasing number of structures in the ensemble. Also, two independent studies recently reported [5,6] concluded that the flexibility solution provided by FlexE does not seem to reflect true flexibility, but FlexE could only be a useful tool for merging different crystal structures and docking into them simultaneously, which saves significant computational time but does not necessarily improve the enrichment. It was also noted that the best result of FlexE was the reproduction of the enrichment given by FlexX, and this was limited to the four-membered ensemble, which is coincident with the results of Steffen et al [4].…”

Section: Introductionmentioning

confidence: 97%

FlexE ensemble docking approach to virtual screening for CDK2 inhibitors

Kim

Park

Chong

2007

Molecular Simulation

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In spite of a proven potential and effectiveness of FlexE in docking flexible ligands into an ensemble of protein structures, FlexE has rarely been successful in virtual screening situations. In this study, we constructed cyclin-dependent kinase 2 (CDK2) ensemble structures which have exactly the same backbone conformations as 1AQ1 but differ only at the side chain torsion angles of the key amino acid (Lys33, Phe80, Lys89 and Asp145) residues: the torsion angles observed in the 17 CDK2 crystal structures were adapted to represent conformational flexibility. FlexE ensemble docking protocol then completely samples the full conformational fields generated by combination of torsions of the four amino acids in the ATP binding site. Virtual screening for CDK2 inhibitors by using the FlexE ensemble docking of a database composed of 48,703 inactives and 82 actives showed significant enrichment factor (EF ¼ 18.5), and successfully identified 71 actives among the top 132 ligands (53.8%) ranked by total energy scores. Moreover, total energy scoring followed by visual inspection filtered-off non-specific binders among the highly-ranked ligands to increase the ratio of actives-to-inactives to 71:13 at the top 5% of the virtual screening solutions.

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“…Therefore, other than the receptor conformations in the starting set, new structures are generated and a more complete "ensemble" is taken into account during the docking experiments. Nevertheless, a recent study has pointed out that the method is not able to deal with large loop rearrangements and that, furthermore, it shows a worse performance in terms of enrichment factor than running multiple docking calculations for each receptor structure [52]. The FLEXE philosophy also underlies the FITTED technique [53] in the representation of receptor flexibility.…”

Section: Including Dynamics In Docking and Drug Designmentioning

confidence: 98%

Molecular Recognition and Drug-Lead Identification: What Can Molecular Simulations Tell Us?

Morra

Genoni²,

Neves

et al. 2010

CMC

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Molecular recognition and ligand binding involving proteins underlie the most important life processes within the cell, such as substrate transport, catalysis, signal transmission, receptor trafficking, gene regulation, switching on and off of biochemical pathways. Despite recent successes in predicting the structures of many protein-substrate complexes, the dynamic aspects of binding have been largely neglected by computational/theoretical investigations. Recently, several groups have started tackling these problems with the use of experimental and simulation methods and developed models describing the variation of protein dynamics upon complex formation, shedding light on how substrate or inhibitor binding can alter protein flexibility and function. The study of ligand-induced dynamic variations has also been exploited to review the concept of allosteric changes, in the absence of major conformational changes. In this context, the study of the influence of protein motions on signal transduction and on catalytic activities has been used to develop pharmacophore models based on ensembles of protein conformations. These models, taking flexibility explicitly into account, are able to distinguish active inhibitors versus nonactive drug-like compounds, to define new molecular motifs and to preferentially identify specific ligands for a certain protein target. The application of these methods holds great promise in advancing structure-based drug discovery and medicinal chemistry in general, opening up the possibility to explore broader chemical spaces than is normally done in an efficient way. In this review, examples illustrating the extent to which simulations can be used to understand these phenomena will be presented along with examples of methodological developments to increase physical understanding of the processes and improve the possibility to rationally design new molecules.

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Ensemble Docking into Flexible Active Sites. Critical Evaluation of FlexE Against JNK‐3 and β‐Secretase.

Abstract: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Cited by 16 publications

References 1 publication

Flexible ligand docking to multiple receptor conformations: a practical alternative

Flexible ligand docking to multiple receptor conformations: a practical alternative

FlexE ensemble docking approach to virtual screening for CDK2 inhibitors

Molecular Recognition and Drug-Lead Identification: What Can Molecular Simulations Tell Us?

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