PDF(Pubmed)
Abstract：
Targeting SARS-CoV-2 papain-like protease using inhibitors is a suitable approach for inhibition of virus replication and dysregulation of host anti-viral immunity. Engaging all five binding sites far from the catalytic site of PLpro is essential for developing a potent inhibitor. We developed and validated a structure-based pharmacophore model with 9 features of a potent PLpro inhibitor. The pharmacophore model-aided virtual screening of the comprehensive marine natural product database predicted 66 initial hits. This hit library was downsized by filtration through a molecular weight filter of ≤ 500 g/mol. The 50 resultant hits were screened by comparative molecular docking using AutoDock and AutoDock Vina. Comparative molecular docking enables benchmarking docking and relieves the disparities in the search and scoring functions of docking engines. Both docking engines retrieved 3 same compounds at different positions in the top 1 % rank, hence consensus scoring was applied, through which CMNPD28766, aspergillipeptide F emerged as the best PLpro inhibitor. Aspergillipeptide F topped the 50-hit library with a pharmacophore-fit score of 75.916. Favorable binding interactions were predicted between aspergillipeptide F and PLpro similar to the native ligand XR8-24. Aspergillipeptide F was able to engage all the 5 binding sites including the newly discovered BL2 groove, site V. Molecular dynamics for quantification of Cα-atom movements of PLpro after ligand binding indicated that it exhibits highly correlated domain movements contributing to the low free energy of binding and a stable conformation. Thus, aspergillipeptide F is a promising candidate for pharmaceutical and clinical development as a potent SARS-CoV-2 PLpro inhibitor.
摘要：
使用抑制剂靶向SARS-CoV-2木瓜蛋白酶样蛋白酶是抑制病毒复制和宿主抗病毒免疫失调的合适方法。参与远离PLpro催化位点的所有五个结合位点对于开发有效的抑制剂是必不可少的。我们开发并验证了基于结构的药效团模型，该模型具有9个特征的有效PLpro抑制剂。综合海洋天然产物数据库的药效团模型辅助虚拟筛选预测了66次初始命中。通过用分子量≤500g/mol的过滤器过滤来缩小该命中文库的尺寸。通过使用AutoDock和AutoDockVina的比较分子对接来筛选50个所得命中。比较分子对接可以实现对标对接，并缓解对接引擎搜索和评分功能的差异。两台对接引擎在前1%排名的不同位置检索到3种相同的化合物，因此采用了共识评分，通过CMNPD28766，曲霉肽F成为最好的PLpro抑制剂。曲霉肽F以75.916的药效基团拟合得分超过50个命中文库。与天然配体XR8-24相似,在曲霉肽F和PLpro之间预测了有利的结合相互作用。曲霉肽F能够接合包括新发现的BL2沟在内的所有5个结合位点，位点V.用于定量配体结合后PLpro的Cα原子运动的分子动力学表明，它表现出高度相关的结构域运动，这有助于低结合自由能和稳定的构象。因此，作为一种有效的SARS-CoV-2PLpro抑制剂，曲霉肽F是药物和临床开发的有希望的候选者。
