Fibroblast activation protein (FAP) is an important target for tumor imaging and theranostic applications, but improving the residence time of FAP inhibitors requires a detailed understanding of how these compounds bind. In this new paper [J. Chem. Inf. Model. (2026), 66, 7179–7189] by Joep W. Wals and coworkers of our UA group, molecular dynamics and QM/MM simulations are used to unravel the covalent binding mechanism of UAMC-1110 to FAP. The calculations reveal a previously unrecognized protonation pathway involving H734 and suggest that dissociation of the covalent complex most plausibly proceeds through hydrolysis. These mechanistic insights may help guide the rational design of FAP inhibitors with prolonged tumor residence times.

Many thanks to Joep W. Wals for the nice work!