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Challenging the gold standard for 3D-QSAR: template CoMFA versus X-ray alignment

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Abstract

X-ray-based alignments of bioactive compounds are commonly used to correlate structural changes with changes in potencies, ultimately leading to three-dimensional quantitative structure–activity relationships such as CoMFA or CoMSIA models that can provide further guidance for the design of new compounds. We have analyzed data sets where the alignment of the compounds is entirely based on experimentally derived ligand poses from X-ray-crystallography. We developed CoMFA and CoMSIA models from these X-ray-determined receptor-bound conformations and compared the results with models generated from ligand-centric Template CoMFA, finding that the fluctuations in the positions and conformations of compounds dominate X-ray-based alignments can yield poorer predictions than those from the self-consistent template CoMFA alignments. Also, when there exist multiple different binding modes, structural interpretation in terms of binding site constraints can often be simpler with template-based alignments than with X-ray-based alignments.

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Acknowledgments

The authors would like to acknowledge Yvonne Martin for providing quality data for the X-ray structures and for helpful comments on the manuscript. The reviewers are thanked for their helpful and constructive comments.

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Authors and Affiliations

  1. Certara, Martin-Kollar-Str. 17, 81829, Munich, Germany

    Bernd Wendt & Richard D. Cramer

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  1. Bernd Wendt
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  2. Richard D. Cramer
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Correspondence to Bernd Wendt.

Appendix

Appendix

See Tables 6, 7, 8, 9, 10, 11 and 12.

Table 6 Urokinase subset model statistics
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Table 7 PTP-1B subset model statistics
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Table 8 Chk1 subset model statistics
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Table 9 Fraction of variance
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Table 10 External validation—predictions for Urokinase test set
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Table 11 External validation—predictions for PTP-1B test set
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Table 12 External validation—predictions for CHK-1 test set
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Wendt, B., Cramer, R.D. Challenging the gold standard for 3D-QSAR: template CoMFA versus X-ray alignment. J Comput Aided Mol Des 28, 803–824 (2014). https://doi.org/10.1007/s10822-014-9761-z

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  • DOI: https://doi.org/10.1007/s10822-014-9761-z

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