Protein Electric Fields Enable Faster and Longer-Lasting Covalent Inhibition of β-Lactamases.

ABSTRACT: The widespread design of covalent drugs has focused on crafting reactive groups of proper electrophilicity and positioning toward targeted amino-acid nucleophiles. We found that environmental electric fields projected onto a reactive chemical bond, an overlooked design element, play essential roles in the covalent inhibition of TEM-1 β-lactamase by avibactam. Using the vibrational Stark effect, the magnitudes of the electric fields that are exerted by TEM active sites onto avibactam's reactive C═O were measured and demonstrate an electrostatic gating effect that promotes bond formation yet relatively suppresses the reverse dissociation. These results suggest new principles of covalent drug design and off-target site prediction. Unlike shape and electrostatic complementary which address bin

SUBMITTER: Ji Z 

PROVIDER: S-EPMC10066720 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature