Generation and selection of novel estrogen receptor ligands using the de novo structure-based design tool, SkelGen.
A de novo design approach to generating novel estrogen receptor (ER) ligands is described. The SkelGen program was used to generate ligands in the active sites of seven crystal structures of ERalpha. Seventeen high-scoring, diverse structures were selected from the SkelGen output and synthesized without introducing any modifications to the structures. Five ligands, four of which are novel, showed < or = 25 microM affinity, with the best compound displaying an IC50 of 340 nM. SkelGen can, therefore, be a powerful tool for designing active molecules.
Firth-Clark
Stuart
S
De Novo Pharmaceuticals Ltd., Compass House, Vision Park, Histon, Cambridge, CB4 9ZR United Kingdom.
Willems
Henriëtte M G
HM
Williams
Anthony
A
Harris
William
W
D001667:Binding, Competitive; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008954:Models, Biological; D015394:Molecular Structure; D011960:Receptors, Estrogen / Q000819:agonists / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012984:Software; D013329:Structure-Activity Relationship
D008024:Ligands; D011960:Receptors, Estrogen; D011994:Recombinant Proteins