ABSTRACT Neprilysin (NEP), a zinc‐dependent metalloprotease involved in the degradation of bioactive peptides, represents a validated target for heart failure therapeutics. In this study, a pharmacophore‐based virtual screening approach combined with biochemical and biophysical assays, alongside molecular dynamics (MD) simulations, was employed to identify novel NEP inhibitors. The pharmacophore model Phar‐A3D2R1 successfully identified pentagalloylglucose (PGG) and tannic acid as potent inhibitors, with IC 50 values of 17.2 ± 1.5 μM and 10.9 ± 0.7 μM, respectively. Local surface plasmon resonance (LSPR) assays confirmed strong binding affinities (KD = 6.2 ± 0.4 μM for PGG and 5.9 ± 0.5 μM for tannic acid). MD simulations revealed stable ligand–enzyme interactions mediated by hydrogen bonding, hydrophobic contacts, electrostatic interactions, and coordination with the catalytic Zn 2+ ion. Cytotoxicity assessment in HEK293T cells indicated negligible toxicity. These results validate PGG and tannic acid as promising lead compounds for NEP inhibition and provide a basis for further structure‐based optimization toward cardiovascular therapeutics.
Kuo et al. (Sun,) studied this question.