Browsing by Author "Shen, TW"

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A pharmacophore-based evolutionary approach for screening estrogen receptor antagonists
(2004)
Yang, JM
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Shen, TW
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生物資訊及系統生物研究所
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Institude of Bioinformatics and Systems Biology
Virtual ligand screening has emerged as a promising approach for drug development. The inaccuracy of the scoring methods is probably major weakness for virtual ligand screening. In this paper, we have developed a pharmacophore-based evolutionary approach that was applicable to virtual screening and post-docking analysis. Our tool, referred to as the Generic Evolutionary Method for molecular DOCKing (GEMDOCK), combines an evolutionary approach and a new pharmacophore-based scoring function for virtual database screening. The former integrates discrete and continuous global search strategies with local search strategies to speed up convergence. The latter integrates a simple empirical scoring function and pharmacophore perferences. We accessed the screening accuracy of our approach on estrogen receptor alpha (ERalpha) using a ligand database on which competing tools were evaluated. The accuracies of our prediction were 0.64 for the GH score and 0.91% for the false positive rate when the true positive rate was 100%. We found that our pharmacophore-based scoring function indeed is able to reduce the number of the false positives. These results suggest that GEMDOCK is robust and can be a useful tool for virtual database screening.
A pharmacophore-based evolutionary approach for screening selective estrogen receptor modulators
(2005-05-01)
Yang, JM
;
Shen, TW
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生物科技學系
;
生物資訊及系統生物研究所
;
Department of Biological Science and Technology
We developed a pharmacophore-based evolutionary approach for virtual screening. This tool, termed the Generic Evolutionary Method for molecular DOCKing (GEMDOCK), combines an evolutionary approach with a new pharmacophore-based scoring function. The former integrates discrete and continuous global search strategies with local search strategies to expedite convergence. The latter, integrating an empirical-based energy function and pharmacological preferences (binding-site pharmacological interactions and ligand preferences), simultaneously serves as the scoring function for both molecular docking and postdocking analyses to improve screening accuracy. We apply pharmacological interaction preferences to select the ligands that form pharmacological interactions with target proteins, and use the ligand preferences to eliminate the ligands that violate the electrostatic or hydrophilic constraints. We assessed the accuracy of our approach using human estrogen receptor (ER) and a ligand database from the comparative studies of Bissantz et al. (J Med Chem 2000;43:4759-4767). Using GEMDOCK, the average goodness-of-hit (GH) score was 0.83 and the average false-positive rate was 0.13% for ER antagonists, and the average GH score was 0.48 and the average false-positive rate was 0.75% for ER agonists. The performance of GEMDOCK was superior to competing methods such as GOLD and DOCK. We found that our pharmacophore-based scoring function indeed was able to reduce the number of false positives; moreover, the resulting pharmacological interactions at the binding site, as well as ligand preferences, were important to the screening accuracy of our experiments. These results suggest that GEMDOCK constitutes a robust tool for virtual database screening. (c) 2005 Wiley-Liss, Inc.
An evolutionary approach with pharmacophore-based scoring functions for virtual database screening
(2004)
Yang, JM
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Shen, TW
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Chen, YF
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Chiu, YY
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生物科技學系
We have developed a new tool for virtual database screening. This tool, referred to as the Generic Evolutionary Method for molecular DOCKing (GEMDOCK), combines an evolutionary approach and a new pharmacophore-based scoring function. The former integrates discrete and continuous global search strategies with local search strategies to speed up convergence. The latter simultaneously serves as the scoring function of both molecular docking and post-docking analysis to improve the number of the true positives. We accessed the accuracy of our approach on HSV-1 thymidine kinase using a ligand database on which competing tools were evaluated. The accuracies of our predictions were 0.54 for the GH score and 1.62% for the false positive rate when the true positive rate was 100%. We found that our pharmacophore-based scoring function indeed is able to reduce the number of the false positives. These results suggest that GEMDOCK is robust and can be a useful tool for virtual database screening.
Consensus scoring criteria for improving enrichment in virtual screening
(2005-07-01)
Yang, JM
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Chen, YF
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Shen, TW
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Kristal, BS
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Hsu, DF
Virtual screening of molecular compound libraries is a potentially powerful and inexpensive method for the discovery of novel lead compounds for drug development. The major weakness of virtual screening-the inability to consistently identify true positives (leads)-is likely due to our incomplete understanding of the chemistry involved in ligand binding and the subsequently imprecise scoring algorithms. It has been demonstrated that combining multiple scoring functions (consensus scoring) improves the enrichment of true positives. Previous efforts at consensus scoring have largely focused on empirical results, but they have yet to provide a theoretical analysis that gives insight into real features of combinations and data fusion for virtual screening. Results: We demonstrate that combining multiple scoring functions improves the enrichment of true positives only if (a) each of the individual scoring functions has relatively high performance and (b) the individual scoring functions are distinctive. Notably, these two prediction variables are previously established criteria for the performance of data fusion approaches using either rank or score combinations. This work, thus, establishes a potential theoretical basis for the probable success of data fusion approaches to improve yields in in silico screening experiments. Furthermore, it is similarly established that the second criterion (b) can, in at least some cases, be functionally defined as the area between the rank versus score plots generated by the two (or more) algorithms. Because rank-score plots are independent of the performance of the individual scoring function, this establishes a second theoretically defined approach to determining the likely success of combining data from different predictive algorithms. This approach is, thus, useful in practical settings in the virtual screening process when the performance of at least two individual scoring functions (such as in criterion a) can be estimated as having a high likelihood of having high performance, even if no training sets are available. We provide initial validation of this theoretical approach using data from five scoring systems with two evolutionary docking algorithms on four targets, thymidine kinase, human dihydrofolate reductase, and estrogen receptors of antagonists and agonists. Our procedure is computationally efficient, able to adapt to different situations, and scalable to a large number of compounds as well as to a greater number of combinations. Results of the experiment show a fairly significant improvement (vs single algorithms) in several measures of scoring quality, specifically "goodness-of-hit" scores, false positive rates, and "enrichment". This approach (available online at http://gemdock.life. nctu.edu.tw/dock/download.php) has practical utility for cases where the basic tools are known or believed to be generally applicable, but where specific training sets are absent.