靶向SARS-CoV-2刺突糖蛋白受体结合域和隐蔽口袋的生物分子模拟
Targeting Receptor Binding Domain and Cryptic Pocket of Spike glycoprotein from SARS-CoV-2 by biomolecular modeling
摘要：
SARS-CoV-2是新冠肺炎（Covid-19）的病原体，迄今已报告约343.5万例人类感染病例，其中包括187个国家的23.9万多例死亡病例，目前尚无有效的治疗方法。为此，有必要探索新的方法来开发能够抑制病毒进入宿主细胞的药物。因此，这项工作包括探索SARS-CoV-2（PDB ID：6VSB）刺突蛋白的潜在抑制化合物，这些化合物从Patogen Box获得。随后，通过虚拟筛选和分子对接技术对它们进行筛选，从而获得了1000个化合物的顶部，这些化合物用于针对位于受体结合结构域（RBD）中的结合位点和位于N-末端结构域（NTD）中的隐蔽位点，从而产生了用于阻断感染的良好的药物靶标。从前1000个化合物中选择最佳化合物（TCMDC-124223）用于结合位点。它与干预识别和随后进入宿主细胞的特定残基相互作用，导致与对照化合物（橙皮苷和大黄素）相比更有利的结合自由能。以相同的方式，选择化合物TCMDC-133766作为隐蔽位点。这些鉴定的化合物是潜在的抑制剂，可用于开发允许有效治疗该疾病的新药。
英文摘要：
SARS-CoV-2, the causative agent of the disease known as Covid-19, has so far reported around 3,435,000 cases of human infections, including more than 239,000 deaths in 187 countries, with no effective treatment currently available. For this reason, it is necessary to explore new approaches for the development of a drug capable of inhibiting the entry of the virus into the host cell. Therefore, this work includes the exploration of potential inhibitory compounds for the Spike protein of SARS-CoV-2 (PDB ID: 6VSB), which were obtained from The Patogen Box. Later, they were filtered through virtual screening and molecular docking techniques, thus obtaining a top of 1000 compounds, which were used against a binding site located in the Receptor Binding Domain (RBD) and a cryptic site located in the N-Terminal Domain (NTD), resulting in good pharmaceutical targets for the blocking the infection. From the top 1000, the best compound (TCMDC-124223) was selected for the binding site. It interacts with specific residues that intervene in the recognition and subsequent entry into the host cell, resulting in a more favorable binding free energy in comparison to the control compounds (Hesperidine and Emodine). In the same way, the compound TCMDC-133766 was selected for the cryptic site. These identified compounds are potential inhibitors that can be used for the development of new drugs that allow effective treatment for the disease.
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