Conformation Driven Enhancement of Neurolysin Activity in Presence of a Small Molecule Activator.

ABSTRACT: Neurolysin (Nln) is an M3 metallopeptidase that regulates neuropeptide concentration in the central nervous system. It has emerged as a therapeutic target for mitigating post-ischemic injury by hydrolyzing and inactivating several neuropeptides. It has been recently shown that small molecule activators, such as pyridine piperazine (Py-Pip) derivatives, can enhance Nln catalytic activity, facilitating hydrolysis of Nln substrate peptides. However, binding sites of these molecules and the mechanism of action remain unclear due to the dynamic nature of Nln. Here, we use molecular dynamics (MD) simulation of the apo and activator-bound Nln systems along with Markov state modeling to identify three binding sites of Py-Pip, and quantify their effects on the Nln conformational landscape and kinet

SUBMITTER: Bose S 

PROVIDER: S-EPMC12803173 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature