title: Consensus Computational Ligand-Based Design for the Identification of Novel Modulators of Human Estrogen Receptor Alpha.
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.
authors.affiliation: 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.
authors.forename: Paul B
authors.initials: PB
authors.lastname: McKay
authors.affiliation: 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. fayned@tcd.ie.
authors.forename: Darren
authors.initials: D
authors.lastname: Fayne
authors.affiliation: IBM Almaden Research Center, San Jose, California, USA.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Horn
authors.affiliation: 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.
authors.forename: Timothy
authors.initials: T
authors.lastname: James
authors.affiliation: 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.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Peters
authors.affiliation: 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.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Carta
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Caboni
authors.affiliation: 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.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nevin
authors.affiliation: 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.
authors.forename: Trevor
authors.initials: T
authors.lastname: Price
authors.affiliation: Trinity Centre for High Performance Computing, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Geoff
authors.initials: G
authors.lastname: Bradley
authors.affiliation: 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.
authors.forename: D Clive
authors.initials: DC
authors.lastname: Williams
authors.affiliation: IBM Almaden Research Center, San Jose, California, USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Rice
authors.affiliation: 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.
authors.forename: David G
authors.initials: DG
authors.lastname: Lloyd
keywords: Consensus screening; Estrogen receptor; Ligand-based drug design; Pharmacophore matching; Virtual screening