Consensus Computational Ligand-Based Design for the Identification of Novel Modulators of Human Estrogen Receptor Alpha

Authors

  • Paul B. McKay,

    1. Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland tel: +353-1-8963527, fax: +353-1-6772400
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  • Darren Fayne,

    Corresponding author
    1. Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland tel: +353-1-8963527, fax: +353-1-6772400
    • Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland tel: +353-1-8963527, fax: +353-1-6772400
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  • Hans W. Horn,

    1. IBM Almaden Research Center, San Jose, California, USA
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  • Timothy James,

    1. Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland tel: +353-1-8963527, fax: +353-1-6772400
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  • Martin B. Peters,

    1. Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland tel: +353-1-8963527, fax: +353-1-6772400
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  • Giorgio Carta,

    1. Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland tel: +353-1-8963527, fax: +353-1-6772400
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  • Laura Caboni,

    1. Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland tel: +353-1-8963527, fax: +353-1-6772400
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  • Daniel K. Nevin,

    1. Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland tel: +353-1-8963527, fax: +353-1-6772400
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  • Trevor Price,

    1. Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland tel: +353-1-8963527, fax: +353-1-6772400
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  • Geoff Bradley,

    1. Trinity Centre for High Performance Computing, Trinity College Dublin, Dublin 2, Ireland
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  • D. Clive Williams,

    1. Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland tel: +353-1-8963527, fax: +353-1-6772400
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  • Julia E. Rice,

    1. IBM Almaden Research Center, San Jose, California, USA
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  • David G. Lloyd

    1. Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland tel: +353-1-8963527, fax: +353-1-6772400
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Abstract

We describe the first targeted validation of fFLASH, a molecular similarity program from IBM that has been previously proposed as suitable for the virtual screening (VS) of compound libraries based on explicit 3D flexible superimpositions, as part of its deployment within a novel consensus ligand-based virtual screening cascade. A virtual screening protocol using fFLASH for the human estrogen receptor alpha (ERα) was advanced and benchmarked against screens completed using established commercial screening softwares – Catalyst and ROCS. The optimised protocol was applied to a ∼6000 member physical screening collection and virtual ‘hits’ sourced and biologically assayed. The approach identified a novel, potent and highly selective partial antagonist of the ERα. This study firstly validates the clique detection algorithm utilised by fFLASH and secondly, emphasises the benefits of the consensus approach of employing more than one program in a VS protocol.

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