Figure 6: Cyclization strategy inspired by the bound bioactive conformation of compound 1.
From: Binding site elucidation and structure guided design of macrocyclic IL-17A antagonists
(A) In solution, lack of an NOE signal from the cyclopentyl and phenyl linker of compound 1 (left) indicated that the bound conformation was not highly populated in solution. Cyclization between the L-phenylalanine side chain and the N,N-dimethylamide (right) may reinforce the bound bioactive conformation (right). (B) Use of MD/MM-GBSA to predict binding affinities in design of macrocyclic compounds. Examples are for the discussed compounds. Box regions correspond to 50% of the distribution, lines extend to max 1.5 times of this interval, and averages are denoted by dashed lines in the boxes. (C) Compound 2 bound to IL-17A. D. Compound 3 bound to IL-17A.
