高須 昌子

Obesity is associated with various metabolic disorders, and pancreatic lipase inhibitors are important therapeutic agents that suppress fat absorption. Quinolone alkaloids isolated from Euodia fruit have been reported to exhibit inhibitory activity against pancreatic lipase. In this study, docking simulations were performed using 33 ligands, including 14 isolated quinolone alkaloids and 19 virtual stereoisomers, against human pancreatic lipase. The ligands were classified into three structural groups based on carbon chain saturation and the presence of hydroxyl groups, and their docking results were compared with experimental activity. Overall, the docking results were consistent with the experimental data, showing positive correlations between structural groups 1 and 3. Notably, Mol 10, which interacted with His151, exhibited a high docking score despite its low experimental activity, whereas Mol 14-1, which interacted with His263, demonstrated strong inhibitory activity and a positive correlation with the docking scores. These findings suggest that the docking score may not always strongly correlate with experimental potency, as it can depend on the docking pose. This study highlights the potential of quinolone alkaloids as pancreatic lipase inhibitors and emphasizes the importance of analyzing ligand-residue interactions.

Pancreatic lipase (PL) is a key enzyme in dietary fat absorption and a validated target for preventing obesity. However, the existing PL inhibitors, such as orlistat, have side effects. We developed a molecular design workflow that integrates machine-learning-based generation with iterative docking simulations, focusing on quinolone-alkaloid-like scaffolds. The docking score of the best candidate decreased from -8.0 to -13.5 kcal/mol over 60 optimization cycles. The top-scoring structure contained a polycyclic aromatic core linked via conjugated chains, with docking poses indicating π–π stacking with Tyr114 and Phe215, consistent with a pocket-blocking mechanism that impeded substrate entry. Additionally, we observed a polar approach near Ser152. The generator produced chemotypes that resembled known inhibitors despite starting from quinolone alkaloid scaffolds. Although we focused on docking-based optimization, these findings demonstrate the potential of AI-assisted molecular design for identifying novel PL inhibitors. Further validation is required, including systematic structure-activity analyses and experimental testing.

Alzheimer's disease is an irreversible neurological disorder for which there are no effective small molecule therapeutics. A phosphodiesterase 5 (PDE5) inhibitor is a candidate medicine for the treatment of Alzheimer's disease. Rutaecarpine, an indole alkaloid found in Euodiae Fructus, has inhibitory activity for PDE5. Euodiae Fructus contains more evodiamine than rutaecarpine. Therefore, we performed molecular dynamics simulations of the complex of PDE5 and evodiamine. The results showed that the PDE5 and (-)-evodiamine complexes were placed inside the reaction center compared to the case of PDE5 and (+)-evodiamine complex. The binding of (-)-evodiamine to PDE5 increased the root-mean-square deviation and radius of gyration of PDE5. In the PDE5 with (-)-evodiamine complex, the value of the root-mean-square fluctuation of the M-loop, which is thought to be important for activity, increased. This result suggests that (-)-evodiamine may have inhibitory activity.

The characteristic shape changes observed in the growth and division of L-form cells have been explained by several theoretical studies and simulations using a vesicle model in which the membrane area increases with time. In those theoretical studies, characteristic shapes such as tubulation and budding were reproduced in a non-equilibrium state, but it was not possible to incorporate deformations that would change the topology of the membrane. We constructed a vesicle model in which the area of the membrane increases using coarse-grained particles and analyzed the changes in the shape of growing membrane by the dissipative particle dynamics (DPD) method. In the simulation, lipid molecules were added to the lipid membrane at regular time intervals to increase the surface area of the lipid membrane. As a result, it was found that the vesicle deformed into a tubular shape or a budding shape depending on the conditions for adding lipid molecules. This suggests that the difference in the place where new lipid molecules are incorporated into the cell membrane during the growth of L-form cells causes the difference in the transformation pathway of L-form cells.