RESUMO
OBJECTIVE: The mitigation of abdominal aortic aneurysm (AAA) growth through pharmaceutical intervention offers the potential to avert the perils associated with AAA rupture and the subsequent need for surgical intervention. Nevertheless, the existing effective drugs for AAA treatment are limited, necessitating a pressing exploration for novel therapeutic medications. METHODS: AAA-related transcriptome data were downloaded from GEO, and differentially expressed genes (DEGs) in AAA tissue were screened for GO and KEGG enrichment analyses. Small molecule compounds and their target proteins with negative connectivity to the AAA expression profile were predicted in the Connectivity Map (CMap) database. Molecular docking and molecular dynamics simulation were performed to predict the binding of the target protein to the small molecule compound, and the MM/GBSA method was used to calculate the binding free energy. Cluster analysis was performed using the cluster tool in the GROMACS package. An AAA cell-free model was built, and CETSA experiments were used to demonstrate the binding ability of small molecules to the target protein in cells. RESULTS: A total of 2244 DEGs in AAA were obtained through differential analysis, and the DEGs were mainly enriched in the tubulin binding biological function and cell cycle pathway. The CMap results showed that Apicidin had a potential therapeutic effect on AAA with a connectivity score of -97.74, and HDAC4 was the target protein of Apicidin. Based on literature, HDAC4-Apicidin was selected as the subsequent research object. The lowest affinity of Apicidin-HDAC4 molecular docking was -8.218 kcal/mol. Molecular dynamics simulation results indicated that Apicidin-HDAC4 could form a stable complex. MM/GBSA analysis showed a total binding free energy of -55.40 ± 0.79 kcal/mol, and cluster analysis showed that there were two main conformational clusters during the binding process, accounting for 22.4% and 57.8%, respectively. Apicidin could form hydrogen bonds with surrounding residues for stable binding. CETSA experiment proved the stable binding ability of Apicidin and HDAC4. CONCLUSION: Apicidin inhibited HDAC4 in AAA and exhibited favorable protein-ligand interactions and stability, making it a potential candidate drug for treating AAA.
RESUMO
High-intensity acoustic waves existing commonly in aeronautical and aerospace vehicles manifest nonlinear propagation behaviors. Large-amplitude vibration and irregular shape of the aerospace vehicles further complicate the acoustic responses. This paper is concerned with numerical analysis of finite-amplitude acoustic responses of complex-shaped vibration objects. The time-dependent effect of the solid boundary position due to the large-amplitude vibration of the objects is considered. A set of first-order differential equations is derived to govern the finite-amplitude acoustic wave. A fourth-order dispersion-relation-preserving finite difference formulation is employed to solve the nonlinear acoustic equations on a fixed Cartesian grid. Acoustic responses of the fluid and the vibration of the complex-shaped object are coupled by considering the compatibility conditions on the fluid-solid interface. A ghost-cell sharp-interface immersed boundary method is utilized to relax the conformity requirement between the computational grid and solid boundary. Numerical filters are employed in the computational procedure to suppress numerical oscillations. The present method is validated through several numerical tests. Numerical analysis of finite-amplitude acoustic responses of a complex-shaped object is performed. The nonlinear effect of a finite-amplitude acoustic wave, the time-dependent effect of solid boundary position, and the coupling effect between them on the propagation behaviors of nonlinear acoustic waves are discussed.