Dataset Information

The scoring bias in reverse docking and the score normalization strategy to improve success rate of target fishing.

ABSTRACT: Target fishing often relies on the use of reverse docking to identify potential target proteins of ligands from protein database. The limitation of reverse docking is the accuracy of current scoring funtions used to distinguish true target from non-target proteins. Many contemporary scoring functions are designed for the virtual screening of small molecules without special optimization for reverse docking, which would be easily influenced by the properties of protein pockets, resulting in scoring bias to the proteins with certain properties. This bias would cause lots of false positives in reverse docking, interferring the identification of true targets. In this paper, we have conducted a large-scale reverse docking (5000 molecules to 100 proteins) to study the scoring bias in reverse docking by DOCK, Glide, and AutoDock Vina. And we found that there were actually some frequency hits, namely interference proteins in all three docking procedures. After analyzing the differences of pocket properties between these interference proteins and the others, we speculated that the interference proteins have larger contact area (related to the size and shape of protein pockets) with ligands (for all three docking programs) or higher hydrophobicity (for Glide), which could be the causes of scoring bias. Then we applied the score normalization method to eliminate this scoring bias, which was effective to make docking score more balanced between different proteins in the reverse docking of benchmark dataset. Later, the Astex Diver Set was utilized to validate the effect of score normalization on actual cases of reverse docking, showing that the accuracy of target prediction significantly increased by 21.5% in the reverse docking by Glide after score normalization, though there was no obvious change in the reverse docking by DOCK and AutoDock Vina. Our results demonstrate the effectiveness of score normalization to eliminate the scoring bias and improve the accuracy of target prediction in reverse docking. Moreover, the properties of protein pockets causing scoring bias to certain proteins we found here can provide the theory basis to further optimize the scoring functions of docking programs for future research.

SUBMITTER: Luo Q

PROVIDER: S-EPMC5308821 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The scoring bias in reverse docking and the score normalization strategy to improve success rate of target fishing.

Luo Qiyao Q Zhao Liang L Hu Jianxing J Jin Hongwei H Liu Zhenming Z Zhang Liangren L

PloS one 20170214 2

Target fishing often relies on the use of reverse docking to identify potential target proteins of ligands from protein database. The limitation of reverse docking is the accuracy of current scoring funtions used to distinguish true target from non-target proteins. Many contemporary scoring functions are designed for the virtual screening of small molecules without special optimization for reverse docking, which would be easily influenced by the properties of protein pockets, resulting in scorin ...[more]

PMID: 28196116

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Project description:BACKGROUND:In drug design, an efficient structure-based optimization of a ligand needs the precise knowledge of the protein-ligand interactions. In the absence of experimental information, docking programs are necessary for ligand positioning, and the choice of a reliable program is essential for the success of such an optimization. The performances of four popular docking programs, Gold, Glide, Surflex and FlexX, were investigated using 100 crystal structures of complexes taken from the Directory of Useful Decoys-Enhanced database. RESULTS:The ligand conformational sampling was rather efficient, with a correct pose found for a maximum of 84 complexes, obtained by Surflex. However, the ranking of the correct poses was not as efficient, with a maximum of 68 top-rank or 75 top-4 rank correct poses given by Glidescore. No relationship was found between either the sampling or the scoring performance of the four programs and the properties of either the targets or the small molecules, except for the number of ligand rotatable bonds. As well, no exploitable relationship was found between each program performance in docking and in virtual screening; a wrong top-rank pose may obtain a good score that allows it to be ranked among the most active compounds and vice versa. Also, to improve the results of docking, the strengths of the programs were combined either by using a rescoring procedure or the United Subset Consensus (USC). Oddly, positioning with Surflex and rescoring with Glidescore did not improve the results. However, USC based on docking allowed us to obtain a correct pose in the top-4 rank for 87 complexes. Finally, nine complexes were scrutinized, because a correct pose was found by at least one program but poorly ranked by all four programs. Contrarily to what was expected, except for one case, this was not due to weaknesses of the scoring functions. CONCLUSIONS:We conclude that the scoring functions should be improved to detect the correct poses, but sometimes their failure may be due to other varied considerations. To increase the chances of success, we recommend to use several programs and combine their results. Graphical abstract Summary of the results obtained by semi-rigid docking of crystallographic ligands. The docking was done on 100 protein-ligand X-ray structures, taken from the DUD-E database, and using four programs, Glide, Gold, Surflex and FlexX. Based on the docking results, we applied our United Subset Consensus method (USC), for which only the top4-rank poses are relevant. The number of complexes for which the best pose is correct, is represented by the gray boxes, the blue and red boxes correspond to the number of complexes with a correct pose ranked as the top 1 or within the top 4. A pose is considered correct when its root-mean-square deviation from the crystal structure is less than 2 Å.

Project description:The development of target-fishing approaches, aimed at identifying the possible protein targets of a small molecule, represents a hot topic in medicinal chemistry. A successful target-fishing approach would allow for the elucidation of the mechanism of action of all therapeutically interesting compounds for which the actual target is still unknown. Moreover, target-fishing would be essential for preventing adverse effects of drug candidates, by predicting their potential off-targets, and it would speed up drug repurposing campaigns. However, due to the huge number of possible protein targets that a small-molecule might interact with, experimental target-fishing approaches are out of reach. In silico target-fishing represents a valuable alternative, and examples of receptor-based approaches, exploiting the large number of crystallographic protein structures determined to date, have been reported in the literature. To the best of our knowledge, no proper evaluation of such approaches is, however, reported yet. In the present work, we extensively assessed the reliability of docking-based target-fishing strategies. For this purpose, a set of X-ray structures belonging to different targets was selected, and a dataset of compounds, including 10 experimentally active ligands for each target, was created. A target-fishing benchmark database was then obtained, and used to assess the performance of 13 different docking procedures, in identifying the correct target of the dataset ligands. Moreover, a consensus docking-based target-fishing strategy was developed and evaluated. The analysis highlighted that specific features of the target proteins could affect the reliability of the protocol, which however, proved to represent a valuable tool in the proper applicability domain. Our study represents the first extensive performance assessment of docking-based target-fishing approaches, paving the way for the development of novel efficient receptor-based target fishing strategies.

Dataset Information

The scoring bias in reverse docking and the score normalization strategy to improve success rate of target fishing.

Publications

The scoring bias in reverse docking and the score normalization strategy to improve success rate of target fishing.

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