Structure-based de novo design of ligands using a three-dimensional model of the insulin receptor.
For the first time, a three-dimensional model of the insulin receptor is used in the de novo design of novel ligands that potentially mimic interactions of insulin at its receptor. Compound 4 competed with insulin as seen in autophosphorylation assays and inhibited up to 68% of IR autophosphorylation at 300 microM of 4 in 3T3IR cells induced by 1 nM insulin. This model provides a basis for the design of potent insulin receptor ligands.
Ontario Cancer Institute, Princess Margaret Hospital, 620 University Ave., Toronto, Ontario, Canada.
Christopher
C
Tan
Lianhu
L
Wei
F Peter
FP
Ottensmeyer
Ira
I
Goldfine
Betty A
BA
Maddux
Cecil C
CC
Yip
Robert A
RA
Batey
Lakshmi P
LP
Kotra
D016475:3T3 Cells; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D007328:Insulin / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D051379:Mice; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D011972:Receptor, Insulin / Q000737:chemistry* / Q000378:metabolism*
D007328:Insulin; D008024:Ligands; D011972:Receptor, Insulin