Molecular insights into SEN177 binding to human glutaminyl cyclase: a combined MD and DFT study.

Aberrant upregulation of human glutaminyl cyclase (hQC) is associated with the onset and progression of neurodegenerative disorders, notably Alzheimer's disease and Huntington's disease. Consequently, inhibition of hQC activity represents a potential avenue for treatment. SEN177, a potent small-molecule hQC inhibitor, has demonstrated notable preclinical efficacy but its binding mechanism remains incompletely understood. Herein, an integrated computational investigation was performed to elucidate the molecular basis of SEN177-hQC recognition. Notably, we implemented an integrated MD-energy decomposition-DFT scheme to rationalize the molecular mechanism of SEN177-hQC recognition. Molecular dynamics simulations indicated that SEN177 binding constrained the intrinsic conformational mobility of hQC, thereby stabilizing the protein-ligand complex. Energy decomposition analyses indicated that the P1 pharmacophore contributed significantly to binding affinity, with key interactions involving hotspot residues D159, E201, E202, W207, and L249. Complementary DFT analyses identified the frontier molecular orbitals and mapped electrophilic and nucleophilic regions that facilitated specific noncovalent contacts. Collectively, these results provide detailed mechanistic insight into the interaction landscape of SEN177 with hQC and provide a conceptual framework for designing more potent and selective hQC-targeting agents.