The structural role of the carbonyl bridge in substituted pyridine derivatives: crystallographic and computational insights towards butyrylcholinesterase recognition

Abstract

The present study is focused on a structure-guided investigation of the pyridine-based scaffold, 1-(3,5-diphenylpyridin-2-yl)ethan-1-one. The study is designed to probe how substitution variation influences the molecular conformation, crystal packing, electronic structure, and biological recognition. The rigid 3,5-diphenyl substitution limits rotational flexibility around the pyridine–carbonyl linkage, providing a structurally defined platform in which substituent-dependent effects are systematically evaluated. Four representative derivatives (MK1–MK4), bearing electron-rich 3,4-dimethoxyphenyl, halogenated dichlorophenyl, hetero aromatic thiophen-2-yl, and extended aromatic naphthyl substituents, were selected to assess substituent-dependent structural variation. Single-crystal X-ray diffraction analysis revealed that MK1, MK2, and MK3 crystallize in the monoclinic space group, whereas the naphthalene-substituted derivative MK4 adopts a triclinic crystal system. The torsional analysis indicates that the carbonyl bridge exhibits substituent-dependent conformational variation. The presence of the carbonyl group (CO) facilitated hydrogen-bond interactions, contributing to overall molecular stabilisation, while also influencing intramolecular charge distribution and potential enzyme binding. Computational DFT analyses revealed differences in π-delocalization and donor–acceptor interactions across the series, with MK3 showing the most consistent electronic interaction. Molecular docking against human butyrylcholinesterase (hBChE), benchmarked against the co-crystal ligand 5HF, identifies MK3 as the compound with the highest binding affinity for the enzyme. Subsequent 100 ns molecular dynamics simulations confirmed that MK3 retained dynamic stability, reflected by reduced ligand R_g, SASA, and MOLSA, indicating compact, solvent-shielded binding. Overall, the structural findings provide insight into how substituent-dependent conformational variation may relate to differences in enzyme binding behaviour across the series.