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Consensus Computational Ligand‐Based Design for the Identification of Novel Modulators of Human Estrogen Receptor Alpha
Author(s) -
McKay Paul B.,
Fayne Darren,
Horn Hans W.,
James Timothy,
Peters Martin B.,
Carta Giorgio,
Caboni Laura,
Nevin Daniel K.,
Price Trevor,
Bradley Geoff,
Williams D. Clive,
Rice Julia E.,
Lloyd David G.
Publication year - 2012
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201100127
Subject(s) - virtual screening , computer science , protocol (science) , computational biology , identification (biology) , drug discovery , alpha (finance) , bioinformatics , data mining , biology , medicine , construct validity , botany , alternative medicine , nursing , pathology , patient satisfaction
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.