Previously, our group predicted commercially available Food and Drug Administration (FDA) approved drugs that can inhibit each step of the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using a deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI). Unfortunately, additional clinically significant treatment options since the approval of remdesivir are scarce. To overcome the current coronavirus disease 2019 (COVID-19) more efficiently, a treatment strategy that controls not only SARS-CoV-2 replication but also the host entry step should be considered. In this study, we used MT-DTI to predict FDA approved drugs that may have strong affinities for the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane protease serine 2 (TMPRSS2) which are essential for viral entry to the host cell. Of the 460 drugs with K_d of less than 100 nM for the ACE2 receptor, 17 drugs overlapped with drugs that inhibit the interaction of ACE2 and SARS-CoV-2 spike reported in the NCATS OpenData portal. Among them, enalaprilat, an ACE inhibitor, showed a K_d value of 1.5 nM against the ACE2. Furthermore, three of the top 30 drugs with strong affinity prediction for the TMPRSS2 are anti-hepatitis C virus (HCV) drugs, including ombitasvir, daclatasvir, and paritaprevir. Notably, of the top 30 drugs, AT1R blocker eprosartan and neuropsychiatric drug lisuride showed similar gene expression profiles to potential TMPRSS2 inhibitors. Collectively, we suggest that drugs predicted to have strong inhibitory potencies to ACE2 and TMPRSS2 through the DTI model should be considered as potential drug repurposing candidates for COVID-19.

中文翻译：

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通过药物-靶点相互作用深度学习模型，以靶点为中心的药物再利用预测人类血管紧张素转换酶 2 (ACE2) 和跨膜蛋白酶丝氨酸亚型 2 (TMPRSS2) 与批准用于 2019 年冠状病毒病 (COVID-19) 治疗的药物相互作用

此前，我们的团队使用基于深度学习的药物-靶标相互作用模型预测，美国食品和药物管理局 (FDA) 批准的市售药物可以抑制严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 复制的每一步。分子转化体-药物靶点相互作用 (MT-DTI)。不幸的是，自瑞德西韦获得批准以来，其他具有临床意义的治疗选择很少。为了更有效地克服当前的 2019 冠状病毒病 (COVID-19)，应考虑一种不仅控制 SARS-CoV-2 复制而且控制宿主进入步骤的治疗策略。在这项研究中，我们使用 MT-DTI 来预测 FDA 批准的药物，这些药物可能对血管紧张素转换酶 2 (ACE2) 受体和跨膜蛋白酶丝氨酸 2 (TMPRSS2) 具有很强的亲和力，这对于病毒进入宿主细胞至关重要。在 ACE2 受体Kd小于 100 nM 的460 种药物中，有 17 种药物与 NCATS OpenData 门户报告的抑制 ACE2 和 SARS _- CoV-2 尖峰相互作用的药物重叠。其中，ACE抑制剂依那普利拉针对ACE2的Kd值为1.5 _nM。此外，对TMPRSS2具有强亲和力预测的前30名药物中，有3种是抗丙型肝炎病毒（HCV）药物，包括ombitasvir、daclatasvir和paritaprevir。值得注意的是，在前 30 名药物中，AT1R 阻断剂依普罗沙坦和神经精神药物麦角乙脲显示出与潜在 TMPRSS2 抑制剂相似的基因表达谱。总的来说，我们建议通过 DTI 模型预测对 ACE2 和 TMPRSS2 具有强抑制效力的药物应被视为潜在的 COVID-19 药物再利用候选药物。