Garland Olivia, Ton Anh-Tien, Moradi Shoeib, Smith Jason R, Kovacic Suzana, Ng Kurtis, Pandey Mohit, Ban Fuqiang, Lee Jaeyong, Vuckovic Marija, Worrall Liam J, Young Robert N, Pantophlet Ralph, Strynadka Natalie C J, Cherkasov Artem
Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada.
Department of Biochemistry and Molecular Biology and Centre for Blood Research, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
J Chem Inf Model. 2023 Apr 10;63(7):2158-2169. doi: 10.1021/acs.jcim.2c01641. Epub 2023 Mar 17.
The rapid global spread of the SARS-CoV-2 virus facilitated the development of novel direct-acting antiviral agents (DAAs). The papain-like protease (PLpro) has been proposed as one of the major SARS-CoV-2 targets for DAAs due to its dual role in processing viral proteins and facilitating the host's immune suppression. This dual role makes identifying small molecules that can effectively neutralize SARS-CoV-2 PLpro activity a high-priority task. However, PLpro drug discovery faces a significant challenge due to the high mobility and induced-fit effects in the protease's active site. Herein, we virtually screened the ZINC20 database with Deep Docking (DD) to identify prospective noncovalent PLpro binders and combined ultra-large consensus docking with two pharmacophore (ph4)-filtering strategies. The analysis of active compounds revealed their somewhat-limited diversity, likely attributed to the induced-fit nature of PLpro's active site in the crystal structures, and therefore, the use of rigid docking protocols poses inherited limitations. The top hits were assessed against recombinant viral proteins and live viruses, demonstrating desirable inhibitory activities. The best compound VPC-300195 (IC: 15 μM) ranks among the top noncovalent PLpro inhibitors discovered through in silico methodologies. In the search for novel SARS-CoV-2 PLpro-specific chemotypes, the identified inhibitors could serve as diverse templates for the development of effective noncovalent PLpro inhibitors.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）病毒在全球的迅速传播推动了新型直接作用抗病毒药物（DAA）的研发。由于木瓜蛋白酶样蛋白酶（PLpro）在处理病毒蛋白和促进宿主免疫抑制方面具有双重作用，它已被认为是DAA的主要SARS-CoV-2靶点之一。这种双重作用使得识别能够有效中和SARS-CoV-2 PLpro活性的小分子成为一项高度优先的任务。然而，由于蛋白酶活性位点的高流动性和诱导契合效应，PLpro药物研发面临重大挑战。在此，我们利用深度对接（DD）对ZINC20数据库进行虚拟筛选，以识别潜在的非共价PLpro结合剂，并将超大一致性对接与两种药效团（ph4）过滤策略相结合。对活性化合物的分析表明它们的多样性有限，这可能归因于晶体结构中PLpro活性位点的诱导契合性质，因此，使用刚性对接协议存在固有局限性。对筛选出的最佳化合物针对重组病毒蛋白和活病毒进行了评估，结果显示出理想的抑制活性。最佳化合物VPC-300195（IC：15 μM）跻身通过计算机方法发现的顶级非共价PLpro抑制剂之列。在寻找新型SARS-CoV-2 PLpro特异性化学类型的过程中，所鉴定的抑制剂可作为开发有效非共价PLpro抑制剂的多样化模板。
