FlexE: efficient molecular docking considering protein structure variations

Claußen, Holger; Buning, Christian; Rarey, Matthias; Lengauer, Thomas

doi:10.1006/jmbi.2001.4551

Cited by 431 publications

(362 citation statements)

References 52 publications

(49 reference statements)

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“…Because it is computationally expensive, few docking programs allow protein flexibility. Notable exceptions are the latest versions of AutoDock [52], FlexE [57], QXP [56], Affinity [58] and the latest version of ICM-Dock [54,55]. The way flexibility is handled differs from program to program.…”

Section: Docking Programs and Their Underlying Algorithmsmentioning

confidence: 99%

Structure-Based Drug Design: Docking and Scoring

Kroemer

2007

CPPS

274

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This review gives an introduction into ligand -receptor docking and illustrates the basic underlying concepts. An overview of different approaches and algorithms is provided. Although the application of docking and scoring has led to some remarkable successes, there are still some major challenges ahead, which are outlined here as well. Approaches to address some of these challenges and the latest developments in the area are presented. Some aspects of the assessment of docking program performance are discussed. A number of successful applications of structure-based virtual screening are described.

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Section: Docking Programs and Their Underlying Algorithmsmentioning

confidence: 99%

Structure-Based Drug Design: Docking and Scoring

Kroemer

2007

CPPS

274

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“…12,14 Recently, the effect of protein flexibility on docking accuracy has been accessed using the "unbound" docking problem, that is, docking ligands to a X-ray structure with no or a different ligand bound. 12 Claussen et al 30 described docking experiments on 10 different proteins each with four or more available X-ray crystal structures with or without ligands bound. They compared a new method (FlexE) for treatment of protein flexibility using a united protein structure constructed from multiple X-ray structures to docking each ligand into all the proteins ("cross-docking") sequentially with FlexX.…”

Section: Introductionmentioning

confidence: 99%

Lessons in Molecular Recognition: The Effects of Ligand and Protein Flexibility on Molecular Docking Accuracy

et al. 2003

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The key to success for computational tools used in structure-based drug design is the ability to accurately place or "dock" a ligand in the binding pocket of the target of interest. In this report we examine the effect of several factors on docking accuracy, including ligand and protein flexibility. To examine ligand flexibility in an unbiased fashion, a test set of 41 ligand-protein cocomplex X-ray structures were assembled that represent a diversity of size, flexibility, and polarity with respect to the ligands. Four docking algorithms, DOCK, FlexX, GOLD, and CDOCKER, were applied to the test set, and the results were examined in terms of the ability to reproduce X-ray ligand positions within 2.0Å heavy atom root-mean-square deviation. Overall, each method performed well (>50% accuracy) but for all methods it was found that docking accuracy decreased substantially for ligands with eight or more rotatable bonds. Only CDOCKER was able to accurately dock most of those ligands with eight or more rotatable bonds (71% accuracy rate). A second test set of structures was gathered to examine how protein flexibility influences docking accuracy. CDOCKER was applied to X-ray structures of trypsin, thrombin, and HIV-1-protease, using protein structures bound to several ligands and also the unbound (apo) form. Docking experiments of each ligand to one "average" structure and to the apo form were carried out, and the results were compared to docking each ligand back to its originating structure. The results show that docking accuracy falls off dramatically if one uses an average or apo structure. In fact, it is shown that the drop in docking accuracy mirrors the degree to which the protein moves upon ligand binding.

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“…Several crystals can be employed to calculate average potential grids to be later employed in ligand docking [11]. Other approaches combinatorially merge flexible parts of different protein structures to generate new conformations [12]. Huang and Zou have proposed an ensemble docking procedure that, after an optimization step, automatically selects the structure where the ligand best fits [13].…”

Section: Introductionmentioning

confidence: 99%

A new method for ligand docking to flexible receptors by dual alanine scanning and refinement (SCARE)

Bottegoni

Kufareva

Totrov

et al. 2008

J Comput Aided Mol Des

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Protein binding sites undergo ligand specific conformational changes upon ligand binding. However, most docking protocols rely on a fixed conformation of the receptor, or on the prior knowledge of multiple conformations representing the variation of the pocket, or on a known bounding box for the ligand. Here we described a general induced fit docking protocol that requires only one initial pocket conformation and identifies most of the correct ligand positions as the lowest score. We expanded a previously used diverse "cross-docking" benchmark to thirty ligand-protein pairs extracted from different crystal structures. The algorithm systematically scans pairs of neighbouring side chains, replaces them by alanines, and docks the ligand to each 'gapped' version of the pocket. All docked positions are scored, refined with original side chains and flexible backbone and re-scored. In the optimal version of the protocol pairs of residues were replaced by alanines and only one best scoring conformation was selected from each 'gapped' pocket for refinement. The optimal SCARE (SCan Alanines and REfine) protocol identifies a near native conformation (under 2Å RMSD) as the lowest rank for 80% of pairs if the docking bounding box is defined by the predicted pocket envelope, and for as many as 90% of the pairs if the bounding box is derived from the known answer with ~5 Å margin as used in most previous publications. The presented fully automated algorithm takes about two hours per pose of a single processor time, requires only one pocket structure and no prior knowledge about the binding site location. Furthermore, the results for conformationally conserved pockets do not deteriorate due to substantial increase of the pocket variability.

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FlexE: efficient molecular docking considering protein structure variations

Cited by 431 publications

References 52 publications

Structure-Based Drug Design: Docking and Scoring

Structure-Based Drug Design: Docking and Scoring

Lessons in Molecular Recognition: The Effects of Ligand and Protein Flexibility on Molecular Docking Accuracy

A new method for ligand docking to flexible receptors by dual alanine scanning and refinement (SCARE)

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