Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, Mississippi 38677, United States.
J Chem Inf Model. 2011 Jun 27;51(6):1376-92. doi: 10.1021/ci1004916. Epub 2011 May 23.
SARS-CoV from the coronaviridae family has been identified as the etiological agent of Severe Acute Respiratory Syndrome (SARS), a highly contagious upper respiratory disease that reached epidemic status in 2002. SARS-3CL(pro), a cysteine protease indispensible to the viral life cycle, has been identified as one of the key therapeutic targets against SARS. A combined ligand and structure-based virtual screening was carried out against the Asinex Platinum collection. Multiple low micromolar inhibitors of the enzyme were identified through this search, one of which also showed activity against SARS-CoV in a whole cell CPE assay. Furthermore, multinanosecond explicit solvent simulations were carried out using the docking poses of the identified hits to study the overall stability of the binding site interactions as well as identify important changes in the interaction profile that were not apparent from the docking study. Cumulative analysis of the evaluated compounds and the simulation studies led to the identification of certain protein-ligand interaction patterns which would be useful in further structure based design efforts.
冠状病毒科的 SARS-CoV 被确定为严重急性呼吸系统综合症（SARS）的病原体，SARS 是一种高度传染性的上呼吸道疾病，于 2002 年达到流行状态。SARS-3CL(pro)，一种对病毒生命周期至关重要的半胱氨酸蛋白酶，已被确定为对抗 SARS 的关键治疗靶点之一。针对 Asinex Platinum 库进行了联合配体和基于结构的虚拟筛选。通过该搜索鉴定出了多种低微摩尔的酶抑制剂，其中一种在全细胞 CPE 测定中也对 SARS-CoV 具有活性。此外，还使用对接构象对鉴定出的命中物进行了多纳秒显式溶剂模拟，以研究结合部位相互作用的整体稳定性，并确定从对接研究中不明显的相互作用谱中的重要变化。对评估化合物的累积分析和模拟研究导致确定了某些蛋白质-配体相互作用模式，这将有助于进一步的基于结构的设计工作。
