Computationally designed peptide macrocycle inhibitors of New Delhi metallo-β-lactamase 1
Vikram Khipple Mulligan, Sean D. Workman, Tianjun Sun, Stephen Rettie, Xinting Li, L.J. Worrall, Timothy W. Craven, Dustin T. King, Parisa Hosseinzadeh, Andrew M. Watkins, P. Douglas Renfrew, Sharon L. Guffy, Jason W. Labonte, Rocco Moretti, Richard Bonneau, N.C.J. Strynadka, David Baker
Abstract
values across seven designed NDM-1- inhibiting peptides. We were able to determine X-ray crystal structures of three of the designed inhibitors in complex with NDM-1, and in all three the conformation of the peptide is very close to the computationally designed model. In two of the three structures, the binding mode with NDM-1 is also very similar to the design model, while in the third, we observed an alternative binding mode likely arising from internal symmetry in the shape of the design combined with flexibility of the target. Although challenges remain in robustly predicting target backbone changes, binding mode, and the effects of mutations on binding affinity, our methods for designing ordered, binding-competent macrocycles should have broad applicability to a wide range of therapeutic targets.