Attacking COVID-19 Progression Using Multi-Drug Therapy for Synergetic Target Engagement.
Attacking COVID-19 Progression Using Multi-Drug Therapy for Synergetic Target Engagement.
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DOI：
10.3390/biom11060787
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发表时间：
2021-05-23
期刊：
影响因子：
5.5
通讯作者：
Caulfield TR
中科院分区：
文献类型：
--
作者：
Coban MA;Morrison J;Maharjan S;Hernandez Medina DH;Li W;Zhang YS;Freeman WD;Radisky ES;Le Roch KG;Weisend CM;Ebihara H;Caulfield TR
COVID-19是一种毁灭性的呼吸道和炎症性疾病，由一种正在人群中迅速传播的新型冠状病毒引起。在过去的12个月里，导致COVID-19的严重急性呼吸系统综合征冠状病毒2 （SARS-CoV-2）已经感染了1.6亿多人（美国占20%），并在全球造成330多万人死亡（美国占20%）。在我们面临近代史上最具挑战性的时期之一时，迫切需要确定能够从多个方面攻击SARS-CoV-2的候选药物。因此，我们启动了一个计算动力学药物管道，使用分子建模、结构模拟、对接和机器学习模型来预测数百万种化合物对两种重要的SARS-CoV-2病毒蛋白及其宿主蛋白相互作用物（s /Ace2、Tmprss2、cathepins L和K以及mpro）的抑制活性，分别阻止病毒的结合、膜融合和复制。总的来说，我们产生了一个结构构象集合，增加了高质量的对接结果，以筛选超过600万种化合物，包括所有fda批准的药物，临床试验药物（1000万种）和额外的3000万种从片段库中选择的化学型。我们的结果产生了350种高价值化合物的初始集合，这些化合物包括新化合物和fda批准的化合物，现在可以在适当的生物模型系统中进行实验测试。我们预计，我们的研究结果将启动筛查活动，并加速发现COVID-19治疗方法。
COVID-19 is a devastating respiratory and inflammatory illness caused by a new coronavirus that is rapidly spreading throughout the human population. Over the past 12 months, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has already infected over 160 million (>20% located in United States) and killed more than 3.3 million people around the world (>20% deaths in USA). As we face one of the most challenging times in our recent history, there is an urgent need to identify drug candidates that can attack SARS-CoV-2 on multiple fronts. We have therefore initiated a computational dynamics drug pipeline using molecular modeling, structure simulation, docking and machine learning models to predict the inhibitory activity of several million compounds against two essential SARS-CoV-2 viral proteins and their host protein interactors—S/Ace2, Tmprss2, Cathepsins L and K, and Mpro—to prevent binding, membrane fusion and replication of the virus, respectively. All together, we generated an ensemble of structural conformations that increase high-quality docking outcomes to screen over >6 million compounds including all FDA-approved drugs, drugs under clinical trial (>3000) and an additional >30 million selected chemotypes from fragment libraries. Our results yielded an initial set of 350 high-value compounds from both new and FDA-approved compounds that can now be tested experimentally in appropriate biological model systems. We anticipate that our results will initiate screening campaigns and accelerate the discovery of COVID-19 treatments.
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DOI：
10.5216/rpt.v47i3.55429
发表时间：
2018-07-01
期刊：
Revista de Patologia Tropical
影响因子：
--
作者：
Barreto Bezerra, Jose Clecildo;Arantes, Morgana Elias;Neves Junior, Bruno
通讯作者：
Neves Junior, Bruno
影响因子：
15.1
作者：
Ando M;Fiesel FC;Hudec R;Caulfield TR;Ogaki K;Górka-Skoczylas P;Koziorowski D;Friedman A;Chen L;Dawson VL;Dawson TM;Bu G;Ross OA;Wszolek ZK;Springer W
通讯作者：
Springer W
影响因子：
14.6
作者：
Abdollahi, Elaheh;Champredon, David;Moghadas, Seyed M.
通讯作者：
Moghadas, Seyed M.
影响因子：
5.5
作者：
Caulfield, Thomas;Coban, Matt;Flores, Samuel Coulbourn
通讯作者：
Flores, Samuel Coulbourn
影响因子：
3
作者：
Caulfield, Thomas;Medina-Franco, Jose L.
通讯作者：
Medina-Franco, Jose L.