Potential Inhibitors for Novel Coronavirus Protease Identified by Virtual Screening of 606 Million Compounds
Potential Inhibitors for Novel Coronavirus Protease Identified by Virtual Screening of 606 Million Compounds
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DOI：
10.3390/ijms21103626
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发表时间：
2020-05-01
影响因子：
5.6
通讯作者：
Lill, Markus A.
中科院分区：
文献类型：
--
作者：
Fischer, Andre;Sellner, Manuel;Lill, Markus A.
新型严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）在中国的迅速爆发，随后在世界各地蔓延，对全球公共卫生构成严重关切。到目前为止，没有特定的药物或疫苗可用于治疗SARS-CoV-2，尽管它与2003年引起类似流行病的SARS-CoV病毒密切相关。因此，仍然迫切需要鉴定和开发针对SARS-CoV-2的特异性抗病毒治疗剂。为了克服病毒感染，抑制对病毒多蛋白的蛋白水解加工至关重要的蛋白酶是常规的治疗策略。为了找到新的抑制剂，我们通过计算筛选了超过6.06亿种化合物的化合物库，用于结合最近解决的SARS-CoV-2主要蛋白酶（M-pro）的晶体结构。对SARS-CoV-2 M-pro抑制剂的如此巨大的化学空间的筛选以前没有报道。在形状筛选之后，应用两个对接方案，随后确定与药代动力学相关的分子描述符以缩小初始命中的数量。接下来，进行分子动力学模拟以验证对接结合模式的稳定性并全面量化配体结合能。在评估潜在的脱靶结合后，我们报告了12种可购买的化合物，其对靶蛋白酶的结合亲和力预测为比共结晶的肽模拟物化合物更有利。为了快速为患者提供持续的治疗干预建议，我们评估了已批准的抗病毒药物和其他蛋白酶抑制剂，以提供9种化合物的药物再利用列表。此外，我们确定了天然化合物（-）-taxifolin和鼠李素作为潜在的抑制剂的M-pro。鼠李素已经在药店上市。
The rapid outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China followed by its spread around the world poses a serious global concern for public health. To this date, no specific drugs or vaccines are available to treat SARS-CoV-2 despite its close relation to the SARS-CoV virus that caused a similar epidemic in 2003. Thus, there remains an urgent need for the identification and development of specific antiviral therapeutics against SARS-CoV-2. To conquer viral infections, the inhibition of proteases essential for proteolytic processing of viral polyproteins is a conventional therapeutic strategy. In order to find novel inhibitors, we computationally screened a compound library of over 606 million compounds for binding at the recently solved crystal structure of the main protease (M-pro) of SARS-CoV-2. A screening of such a vast chemical space for SARS-CoV-2 M-pro inhibitors has not been reported before. After shape screening, two docking protocols were applied followed by the determination of molecular descriptors relevant for pharmacokinetics to narrow down the number of initial hits. Next, molecular dynamics simulations were conducted to validate the stability of docked binding modes and comprehensively quantify ligand binding energies. After evaluation of potential off-target binding, we report a list of 12 purchasable compounds, with binding affinity to the target protease that is predicted to be more favorable than that of the cocrystallized peptidomimetic compound. In order to quickly advise ongoing therapeutic intervention for patients, we evaluated approved antiviral drugs and other protease inhibitors to provide a list of nine compounds for drug repurposing. Furthermore, we identified the natural compounds (-)-taxifolin and rhamnetin as potential inhibitors of M-pro. Rhamnetin is already commercially available in pharmacies.