Diverse, High-Quality Test Set for the Validation of Protein−Ligand Docking Performance

Hartshorn, Michael J.; Verdonk, Marcel L.; Chessari, Gianni; Brewerton, Suzanne; Mooij, Wijnand T. M.; Mortenson, Paul N.; Murray, Christopher W.

doi:10.1021/jm061277y

Cited by 560 publications

(646 citation statements)

References 102 publications

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“…The future algorithms would benefit from at least an order of magnitude larger high quality cross docking benchmarks that are now available [34] or under development [Kufareva et al, manuscript in preparation]. Overall, we believe that SCARE represents a reliable and practical unbiased "induced fit" docking protocol to assist rational structure based drug design, optimization and virtual screening efforts.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The recent paper by Hartshorn et al makes this point as well as part of a broader discussion of the proper selection of complexes on which to carry out docking algorithm testing [48]. They have constructed a set in which all structures are very highquality.…”

Section: Fairness Of Comparisonsmentioning

confidence: 99%

Surflex-Dock 2.1: Robust performance from ligand energetic modeling, ring flexibility, and knowledge-based search

Jain

2007

J Comput Aided Mol Des

544

502

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The Surflex flexible molecular docking method has been generalized and extended in two primary areas related to the search component of docking. First, incorporation of a small-molecule force-field extends the search into Cartesian coordinates constrained by internal ligand energetics. Whereas previous versions searched only the alignment and acyclic torsional space of the ligand, the new approach supports dynamic ring flexibility and allatom optimization of docked ligand poses. Second, knowledge of well established molecular interactions between ligand fragments and a target protein can be directly exploited to guide the search process. This offers advantages in some cases over the search strategy where ligand alignment is guided solely by a ''protomol'' (a pre-computed molecular representation of an idealized ligand). Results are presented on both docking accuracy and screening utility using multiple publicly available benchmark data sets that place Surflex's performance in the context of other molecular docking methods. In terms of docking accuracy, Surflex-Dock 2.1 performs as well as the best available methods. In the area of screening utility, Surflex's performance is extremely robust, and it is clearly superior to other methods within the set of cases for which comparative data are available, with roughly double the screening enrichment performance.

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“…These results clearly show the potential application of G-LoSA to template-based ligand modeling for de novo ligand design. Here, we evaluate the ability of the new G-LoSA in identifying template ligands and compare the performance with the earlier version, using the same benchmark set (75 targets from the Astex diverse set 26 ). The BS structure of each benchmark target was defined by a cutoff of 4.5 Å from the cognate ligand and used as a query BS structure to search for template ligands from the ligand BS structure library.…”

Section: Comparison With Previous G-losa In Identification Of Ligand mentioning

confidence: 99%

G‐LoSA: An efficient computational tool for local structure‐centric biological studies and drug design

Lee

2016

Protein Science

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Molecular recognition by protein mostly occurs in a local region on the protein surface. Thus, an efficient computational method for accurate characterization of protein local structural conservation is necessary to better understand biology and drug design. We present a novel local structure alignment tool, G-LoSA. G-LoSA aligns protein local structures in a sequence order independent way and provides a GA-score, a chemical feature-based and size-independent structure similarity score. Our benchmark validation shows the robust performance of G-LoSA to the local structures of diverse sizes and characteristics, demonstrating its universal applicability to local structure-centric comparative biology studies. In particular, G-LoSA is highly effective in detecting conserved local regions on the entire surface of a given protein. In addition, the applications of GLoSA to identifying template ligands and predicting ligand and protein binding sites illustrate its strong potential for computer-aided drug design. We hope that G-LoSA can be a useful computational method for exploring interesting biological problems through large-scale comparison of protein local structures and facilitating drug discovery research and development. G-LoSA is freely available to academic users at http://im.compbio.ku.edu/GLoSA/.

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Diverse, High-Quality Test Set for the Validation of Protein−Ligand Docking Performance

Cited by 560 publications

References 102 publications

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

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

Surflex-Dock 2.1: Robust performance from ligand energetic modeling, ring flexibility, and knowledge-based search

G‐LoSA: An efficient computational tool for local structure‐centric biological studies and drug design

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