埃博拉病毒(EBOV)仍然具有很高的传染性,并在灵长类动物中引起严重的出血热。然而,没有监管批准的抗埃博拉病毒病(EVD)的药物。EVD的高毒性和致死性突出了开发治疗剂的需要。病毒蛋白40kDa(VP40),感染过程中表达最丰富的蛋白质,协调装配,萌芽,并将病毒颗粒释放到宿主细胞中。它还调节病毒转录和RNA复制。这项研究试图通过使用计算机模拟方法靶向N末端结构域来鉴定可能潜在地抑制VP40蛋白的小分子。确定了AutoDockVina区分抑制剂和诱饵的能力的统计质量,受试者工作特征曲线(AUC-ROC)曲线下面积为0.791。共有29,519种来自中国和非洲来源的天然产物衍生化合物以及2738种批准的药物成功地针对VP40进行了筛选。使用-8kcal/mol的阈值,来自AfroDb的总共7、11、163和30种化合物,北非天然产品数据库(NANPDB)中药(TCM),和批准的药物图书馆,分别,分子对接后获得。先导化合物的生物活性预测表明其潜在的抗病毒特性。此外,基于随机森林和支持向量机的算法预测化合物抗埃博拉,IC50值在微摩尔范围内(小于25μM)。共有42种天然产物衍生的化合物被鉴定为潜在的EBOV抑制剂,具有理想的ADMET谱,包含1、2和39种来自NANPDB(2-羟基戊烯内酯)的化合物,AfroDb(ZINC000034518176和ZINC000095485942),和中医,分别。共有23种批准的药物,包括多拉菌素,glecaprevir,velpatasvir,ledipasvir,阿维菌素B1,醋酸纳法瑞林,danoprevir,eltrombopag,lanatosideC,和甘草酸,其中,还预测具有潜在的抗EBOV活性,可以进一步探索,以便它们可以重新用于EVD治疗。分子动力学模拟与分子力学泊松-玻尔兹曼表面积计算相结合,证实了配合物的稳定性和良好的结合亲和力(-46.97至-118.9kJ/mol)。潜在的先导化合物在实验测试后可能具有被开发为抗EBOV药物的潜力。
The Ebola virus (EBOV) is still highly infectious and causes severe hemorrhagic fevers in primates. However, there are no regulatorily approved drugs against the Ebola virus disease (EVD). The highly virulent and lethal nature of EVD highlights the need to develop therapeutic agents. Viral protein 40 kDa (VP40), the most abundantly expressed protein during infection, coordinates the assembly, budding, and release of viral particles into the host cell. It also regulates viral transcription and RNA replication. This
study sought to identify small molecules that could potentially inhibit the VP40 protein by targeting the N-terminal domain using an in silico approach. The statistical quality of AutoDock Vina\'s capacity to discriminate between inhibitors and decoys was determined, and an area under the curve of the receiver operating characteristic (AUC-ROC) curve of 0.791 was obtained. A total of 29,519 natural-product-derived compounds from Chinese and African sources as well as 2738 approved drugs were successfully screened against VP40. Using a threshold of -8 kcal/mol, a total of 7, 11, 163, and 30 compounds from the AfroDb, Northern African Natural Products Database (NANPDB), traditional Chinese medicine (TCM), and approved drugs libraries, respectively, were obtained after molecular docking. A biological activity prediction of the lead compounds suggested their potential antiviral properties. In addition, random-forest- and support-vector-machine-based algorithms predicted the compounds to be anti-Ebola with IC50 values in the micromolar range (less than 25 μM). A total of 42 natural-product-derived compounds were identified as potential EBOV inhibitors with desirable ADMET profiles, comprising 1, 2, and 39 compounds from NANPDB (2-hydroxyseneganolide), AfroDb (ZINC000034518176 and ZINC000095485942), and TCM, respectively. A total of 23 approved drugs, including doramectin, glecaprevir, velpatasvir, ledipasvir, avermectin B1, nafarelin acetate, danoprevir, eltrombopag, lanatoside C, and glycyrrhizin, among others, were also predicted to have potential anti-EBOV activity and can be further explored so that they may be repurposed for EVD treatment. Molecular dynamics simulations coupled with molecular mechanics Poisson-Boltzmann surface area calculations corroborated the stability and good binding affinities of the complexes (-46.97 to -118.9 kJ/mol). The potential lead compounds may have the potential to be developed as anti-EBOV drugs after experimental testing.