Molecular aggregation state of bioactive compounds plays a key role in bio-interactive procedure. Diverse aggregation states of bioactive compounds contribute to different biological or chemical properties. Water-bridge, as the simple hetero-molecular aggregation, has been found bridging the binding between many bioactive compounds and their targets through hydrogen bonding network, e.g. in the recognition of neonicotinoids with insect nAChRs. To better understanding the roles of water-bridge on bioactivities of compounds, an approach of hetero-dimeric aggregation with water was proposed. Quantitative structure-activity relationship (QSAR) and pharmacophore modeling investigations were applied on 19 neonicotinoids, as well as their aggregates with water. The aggregate-based CoMSIA, PHASE and linear QSAR models presented better statistical significance and predictabilities than the monomer ones, which indicated that the bioactivities correlated with the aggregate properties and water bridged hydrogen bond of the active site. All results revealed the essential roles of water-bridge in ligand recognition, which should be considered in future ligand design and optimization.

Ligands binding at the benzodiazepine site of GABA_A receptor play important pharmacological roles in clinical application. In this study, ligand-based pharmacophore modeling, 3D-QSAR analysis, and Bayesian model studies have been performed on a set of 84 diverse ligands binding at the benzodiazepine site. The results showed the best pharmacophore hypothesis AADHR.4, which included two hydrogen acceptors (A), one hydrogen donor (D), one hydrophobic group (H), and one aromatic ring (R). Atom-based 3D-QSAR model was built, and it showed good statistical significance (R² = 0.936) and excellent predictive ability (Q² = 0.821). Moreover, Bayesian model was developed and used to identify the key molecular features which are good or bad for the ligand binding activity. All the results from the pharmacophore, 3D-QSAR, and Bayesian modeling studies revealed that a hydrogen-bond donor (e.g., N-H) and a hydrophobic group (e.g., Br) are critical structural features for the ligands binding at the benzodiazepine site.

Eight novel neonicotinoids N-oxide analogues were designed and synthesized. All the compounds have been identified by ¹H NMR and HRMS. The N-oxide analogues exhibit high insecticidal activity against cowpea aphids (Aphis craccivora) at 250 mg·L⁻¹. The influence of N-oxide formation on the biological activity was elucidated by computational chemical study, and it indicated that the water bridge hydrogen bonding network was broken due to the influence of the O atom connected with the pyridine ring.

To investigate whether free cyclooctatetraene dianion (COT²⁻) is aromatic, quantum chemistry methods were used to optimize its structure. Based on the optimized structures, the natural population analysis (NPA) charge, bond order, delocalization energy, nucleus-independent chemical shift (NICS), and harmonic oscillator model of aromaticity (HOMA) values were computed by DFT-B3LYP method with basis set 6-311++G**, which shows that COT²⁻ is not aromatic as it is not planar and has different bond lengths and bond orders, smallest delocalization energy and positive NICS values. To further confirm the finding, the changes of NICS and energy against ring distortion angle were scanned. The COT²⁻ has positive NICS values all along the angle from 180° to 120° while other aromatic systems always have negative values. The energy scanning suggests that COT²⁻ should have the weakest capability to maintain its planar structure. All the calculations strongly indicate that COT²⁻ is not aromatic. This study also suggests that NICS scan might be a good approach to judge aromaticity.