Chen Xinyue, Zhou Bo, Jiang Xinyi, Zhong Huayu, You Aijing, Zou Taiyan, Zhou Chengcheng, Liu Xiaoxiao, Zhang Yonghong
Chongqing Key Research Laboratory for Drug Metabolism, College of Pharmacy, Chongqing Medical University, Chongqing, China.
Department of Pharmacy, Children's Hospital of Chongqing Medical University, Chongqing, China.
Front Pharmacol. 2024 Oct 1;15:1428925. doi: 10.3389/fphar.2024.1428925. eCollection 2024.
Given that there is currently no clinically approved drug or vaccine for parainfluenza 3 (PIV3), we applied a drug repurposing method based on disease similarity and chemical similarity to screen 2,585 clinically approved chemical drugs using PIV3 potential drugs BCX-2798 and zanamivir as our controls. Twelve candidate drugs were obtained after being screened with good disease similarity and chemical similarity ( > 0.50, > 0.56). When docking them with the PIV3 target protein, hemagglutinin-neuraminidase (HN), only oseltamivir was docked with a better score than BCX-2798, which indicates that oseltamivir has an inhibitory effect on PIV3. After the distance ( ) between the drug target of 14 drugs and the PIV3 disease target was measured by the network proximity method based on the PIV3 disease module, it was found that the values of amikacin, oseltamivir, ribavirin, and streptomycin were less than those of the control. Thus, oseltamivir is the best potential drug because it met all the above screening requirements. Additionally, to explore whether oseltamivir binds to HN stably, molecular dynamics simulation of the binding of oseltamivir to HN was carried out, and the results showed that the value of the complex tended to be stable within 100 ns, and the binding free energy of the complex was low (-10.60 kcal/mol). It was proved that oseltamivir screened by our drug repurposing method had the potential feasibility of treating PIV3.
鉴于目前尚无临床批准的针对副流感病毒3型（PIV3）的药物或疫苗，我们应用了一种基于疾病相似性和化学相似性的药物再利用方法，以PIV3潜在药物BCX-2798和扎那米韦作为对照，筛选2585种临床批准的化学药物。经筛选，获得了12种具有良好疾病相似性和化学相似性（>0.50，>0.56）的候选药物。当将它们与PIV3靶蛋白血凝素神经氨酸酶（HN）对接时，只有奥司他韦的对接得分优于BCX-2798，这表明奥司他韦对PIV3具有抑制作用。基于PIV3疾病模块，通过网络接近度方法测量了14种药物的药物靶点与PIV3疾病靶点之间的距离（），发现阿米卡星、奥司他韦、利巴韦林和链霉素的 值低于对照。因此，奥司他韦是最佳潜在药物，因为它满足了上述所有筛选要求。此外，为了探究奥司他韦是否能与HN稳定结合，对奥司他韦与HN的结合进行了分子动力学模拟，结果表明复合物的 值在100 ns内趋于稳定，且复合物的结合自由能较低（-10.60 kcal/mol）。证明了通过我们的药物再利用方法筛选出的奥司他韦具有治疗PIV3的潜在可行性。
