3D-QSAR using `Multiconformer' alignment: The use of HASL in the analysis of 5-HT1A thienopyrimidinone ligands† | Journal of Computer-Aided Molecular Design
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3D-QSAR using `Multiconformer' alignment: The use of HASL in the analysis of 5-HT1A thienopyrimidinone ligands†

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Abstract

The observed 5-HT1A and α1-adrenergic receptor (α1-AR) receptor binding properties of a series of 23 thienopyrimidinones were used to develop HASL 3D-QSAR models. A single, low energy conformer of the most active analogue in the series, which was consistent with NMR structural studies, was chosen as a template molecule. Alignments of all the molecules to the template were provided by an Amber/MM2 superposition force field. In this manner, each molecule was represented by five separate low energy conformers which were subsequently used in the generation of HASL 3D-QSAR models. Models derived from multiple conformers were found to exhibit enhanced predictivity compared to models based on single, low energy conformers. In addition, the use of contour imaging of HASL multi-conformer model interactions was found to lead to a more consistent interpretation of those molecular features most significant for 5-HT1A receptor binding.

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Authors and Affiliations

  1. Dipartimento di Scienze Farmaceutiche, Università di Catania, viale Andrea Doria 6, Ed. 12, Città Universitaria, I-95125 , Catania, Italy

    Salvatore Guccione

  2. Pharmaceutical Research Institute, Macromolecular Structure-CADD, Bristol-Myers Squibb, P.O. Box 4000, Princeton, NJ , 08543, U.S.A.

    Arthur M. Doweyko

  3. Laboratory of Computer Chemistry, Institute of Chemical Metallurgy, Chinese Academy of Science, Beijing , 100081, P.R. China

    Hongming Chen

  4. Centro CNR di Studio per le Macromolecole Stereordinate ed Otticamente Attive, Università di Pisa, via Risorgimento 35, I-56126, Pisa, Italy

    Gloria Uccello Barretta & Federica Balzano

Authors
  1. Salvatore Guccione
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  2. Arthur M. Doweyko
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  3. Hongming Chen
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  4. Gloria Uccello Barretta
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  5. Federica Balzano
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Guccione, S., Doweyko, A.M., Chen, H. et al. 3D-QSAR using `Multiconformer' alignment: The use of HASL in the analysis of 5-HT1A thienopyrimidinone ligands†. J Comput Aided Mol Des 14, 647–657 (2000). https://doi.org/10.1023/A:1008136325544

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  • DOI: https://doi.org/10.1023/A:1008136325544

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