The SARS-CoV-2 main protease (M^pro) is an attractive target towards discovery of drugs to treat COVID-19 because of its key role in virus replication. The atomic structure of M^pro in complex with an α-ketoamide inhibitor (Lig13b) is available (PDB ID:6Y2G). Using 6Y2G and the prior knowledge that protease inhibitors could eradicate COVID-19, we designed a computational study aimed at identifying FDA-approved drugs that could interact with M^pro. We searched the DrugBank and PubChem for analogs and built a virtual library containing ∼33,000 conformers. Using high-throughput virtual screening and ligand docking, we identified Isavuconazonium, a ketoamide inhibitor (α-KI) and Pentagastrin as the top three molecules (Lig13b as the benchmark) based on docking energy. The ΔG_bind of Lig13b, Isavuconazonium, α-KI, Pentagastrin was −28.1, −45.7, −44.7, −34.8 kcal/mol, respectively. Molecular dynamics simulation revealed that these ligands are stable within the M^pro active site. Binding of these ligands is driven by a variety of non-bonded interaction, including polar bonds, H-bonds, van der Waals and salt bridges. The overall conformational dynamics of the complexed-M^pro was slightly altered relative to apo-M^pro. This study demonstrates that three distinct classes molecules, Isavuconazonium (triazole), α-KI (ketoamide) and Pentagastrin (peptide) could serve as potential drugs to treat patients with COVID-19.

SARS-CoV-2主蛋白酶（M ^pro）由于发现其在病毒复制中的关键作用而成为发现治疗COVID-19的药物的诱人靶标。M ^pro与α-酮酰胺抑制剂（Lig13b）形成复合物的原子结构可用（PDB ID：6Y2G）。利用6Y2G和蛋白酶抑制剂可以消除COVID-19的先验知识，我们设计了一项计算研究，旨在鉴定可与M ^pro相互作用的FDA批准药物。我们在DrugBank和PubChem中搜索了类似物，并建立了一个包含约33,000个构象体的虚拟文库。使用高通量虚拟筛选和配体对接，基于对接能，我们确定了Isavuconazonium，一种酮酰胺抑制剂（α-KI）和Pentagastrin作为排名前三的分子（以Lig13b为基准）。该Δ ģ_绑定Lig13b，Isavuconazonium，α-KI的，五肽胃泌素是-28.1，-45.7，-44.7，-34.8千卡/摩尔，分别。分子动力学模拟表明，这些配体在M ^pro活性位点内是稳定的。这些配体的结合受多种非键相互作用的驱动，包括极性键，氢键，范德华力和盐桥。Complexed-M ^pro的整体构象动力学相对于apo-M ^pro略有改变。这项研究表明，三个不同类别的分子，Isavuconazonium（三唑），α-KI（酮酰胺）和Pentagastrin（肽）可以用作治疗COVID-19患者的潜在药物。