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Evaluation of extended parameter sets for the 3D-QSAR technique MaP: Implications for interpretability and model quality exemplified by antimalarially active naphthylisoquinoline alkaloids

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Abstract

The 3D-QSAR technique MaP (Mapping Property distributions of molecular surfaces) characterises biologically active compounds in terms of the distribution of their surface properties (H-bond donor, H-bond acceptor, hydrophilic, weakly hydrophobic, strongly hydrophobic). The MaP descriptor is alignment-independent and yields chemically intuitive models. In this study, the impact of different operational parameters on the interpretability and model quality was investigated. Based on a set of antimalarially active naphtylisoquinoline alkaloids the effect of hydrophobicity assignment as well as the differentiation of H-bond propensity was evaluated according to a full factorial design. It turns out, that including different categories for H-bond donor strength significantly improved interpretability, reduced model complexity, and made possible the derivation of a novel pharmacophore hypothesis for this dataset. Further analysis of the factorial design reveals, that MaP models are robust to parameter changes and generate consistent models for different parameter settings.

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Authors and Affiliations

  1. Department of Pharmacy and Food Chemistry, University of Würzburg, D-97074, Am Hubland, Würzburg, Germany

    Nikolaus Stiefl & Knut Baumann

  2. Institute of Organic Chemistry, University of Würzburg, D-97074, Am Hubland, Würzburg, Germany

    Gerhard Bringmann & Christian Rummey

Authors
  1. Nikolaus Stiefl
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  2. Gerhard Bringmann
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  3. Christian Rummey
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  4. Knut Baumann
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Stiefl, N., Bringmann, G., Rummey, C. et al. Evaluation of extended parameter sets for the 3D-QSAR technique MaP: Implications for interpretability and model quality exemplified by antimalarially active naphthylisoquinoline alkaloids. J Comput Aided Mol Des 17, 347–365 (2003). https://doi.org/10.1023/A:1026125706388

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