Target specific virtual screening: optimization of an estrogen receptor screening platform.
In this work, we introduce a four-step scoring and filtering procedure, furnishing target specific virtual screening (TS-VS), which serves to minimize false positives resulting from conformational artifacts of the docking process and is optimized to converge on novel chemotypes of estrogen receptor alpha (ERalpha). As a proof of concept, VS of a commercial compound database was undertaken (SPECs database release: Aug 2005, 202 054 compounds in total), resulting in the identification of both previously known and novel putative ER scaffolds. Application of distance constraints within TS-VS allowed facile identification of three novel active ligands with ERalpha binding affinities (IC50) of 1.4 microM, 57 nM, and 53 nM. Importantly, they all exhibited ERalpha over ERbeta selectivity, with the most selective being 17-fold. The ligands also displayed low micomolar antiproliferative activity (7-15 microM) in the human MCF-7 breast cancer cell line.
Knox
Andrew J S
AJ
Molecular Design Group, School of Biochemistry and Immunology, Trinity College Dublin, College Green, Dublin 2, Ireland.
Meegan
Mary J
MJ
Sobolev
Vladimir
V
Frost
Dermot
D
Zisterer
Daniela M
DM
Williams
D Clive
DC
Lloyd
David G
DG
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D016477:Artifacts; D001665:Binding Sites; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D016208:Databases, Factual; D004354:Drug Screening Assays, Antitumor; D020847:Estrogen Receptor Modulators / Q000737:chemistry* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000737:chemistry
D000970:Antineoplastic Agents; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D013629:Tamoxifen; C016601:afimoxifene