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Composite multi-parameter ranking of real and virtual compounds for design of MC4R agonists: Renaissance of the Free-Wilson methodology

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Abstract

Drug design is a multi-parameter task present in the analysis of experimental data for synthesized compounds and in the prediction of new compounds with desired properties. This article describes the implementation of a binned scoring and composite ranking scheme for 11 experimental parameters that were identified as key drivers in the MC4R project. The composite ranking scheme was implemented in an AstraZeneca tool for analysis of project data, thereby providing an immediate re-ranking as new experimental data was added. The automated ranking also highlighted compounds overlooked by the project team. The successful implementation of a composite ranking on experimental data led to the development of an equivalent virtual score, which was based on Free-Wilson models of the parameters from the experimental ranking. The individual Free-Wilson models showed good to high predictive power with a correlation coefficient between 0.45 and 0.97 based on the external test set. The virtual ranking adds value to the selection of compounds for synthesis but error propagation must be controlled. The experimental ranking approach adds significant value, is parameter independent and can be tuned and applied to any drug discovery project.

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Acknowledgments

Thanks to Thomas Leek for providing statistics for the chromatographic LogD74 model. Stephan Hjorth is acknowledged for strong support during the development of the models. Alleyn Plowright, Christian Tyrchan, Anders Hogner and Niklas Blomberg are acknowledged for constructive criticism of the manuscript.

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Authors and Affiliations

  1. CVGI AstraZeneca R&D Mölndal, 431 83, Mölndal, Sweden

    Ingemar Nilsson & Magnus O. Polla

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  1. Ingemar Nilsson
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  2. Magnus O. Polla
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Correspondence to Ingemar Nilsson.

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Nilsson, I., Polla, M.O. Composite multi-parameter ranking of real and virtual compounds for design of MC4R agonists: Renaissance of the Free-Wilson methodology. J Comput Aided Mol Des 26, 1143–1157 (2012). https://doi.org/10.1007/s10822-012-9605-7

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  • DOI: https://doi.org/10.1007/s10822-012-9605-7

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