Chemical Biology Lab I, Institute of Advanced Study in Science and Technology, Paschim Boragaon, Guwahati-35, Assam, India.
JSS College of Pharmacy, Department of Pharmaceutical Chemistry, Ooty, 643001, Tamilnadu, India.
Eur J Pharm Sci. 2021 Jul 1;162:105820. doi: 10.1016/j.ejps.2021.105820. Epub 2021 Mar 26.
A new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a respiratory infection out broke in December 2019 in Wuhan, Hubei province, China, resulted in pandemic conditions worldwide. COVID-19 spread swiftly around the world over with an alert of an emergency for an adequate drug. Therefore, in this research, we repurposed the FDA-approved medicines to find the prominent drug used to cure the COVID infected patients. We performed homology modeling of the transmembrane serine protease 2 (TMPRSS2), responsible for the viral entry. The prediction of the transmembrane region and the Conserved Domain in TMPRSS2 protein was made for docking. 4182 FDA-approved compounds from the ZINC database were downloaded and used for the calculation of physicochemical properties. Two thousand eight hundred fifteen screened compounds were used for molecular docking against the modelled protein structure. From which top hit compounds based on binding energy were extracted. At 1 site pose, ZINC3830554 showed the highest binding energy -12.91kcal/mol by forming Salt Bridge at LYS143, Hydrogen bond at ALA8, VAL45, HIS47, SER142, ASN277, ASN359, and TRP363. The hydrophobic Interactions at PHE3, LEU4, ALA7, ALA8, ALA139, PRO197, and PHE266. In the 2 site pose, ZINC203686879 shows the highest binding energy (-12.56 kcal/mol) and forms a hydrophobic interaction with VAL187, VAL189, HIS205, LYS301, GLN347, TRP370 and hydrogen bond was at GLY300, THR302, GLN347, SER350 residues. These hit compounds were subjected to stability checks between the protein-ligand complex through the dynamics simulation (MD), and binding free energy was calculated through the Molecular Mechanics energies combined with Poisson-Boltzmann (MM/PBSA) method. We hope that hit compounds would be an efficient inhibitor that can block the TMPRSS2 activity and resist the entry of the SARS-CoV-2 virus into targeted human cells by reducing the virus's infectivity and transmissibility.
一种新型严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2）于 2019 年 12 月在中国湖北省武汉市爆发，引发了全球范围内的大流行。COVID-19 在全球迅速传播，人们对寻找有效的治疗药物发出了紧急警报。因此，在本研究中，我们将已获美国食品药品监督管理局（FDA）批准的药物重新用于寻找可治疗 COVID 感染患者的有效药物。我们对负责病毒进入的跨膜丝氨酸蛋白酶 2（TMPRSS2）进行同源建模。对 TMPRSS2 蛋白的跨膜区域和保守结构域进行预测，以便进行对接。从 ZINC 数据库中下载了 4182 种 FDA 批准的化合物，并用于计算物理化学性质。对 2815 种筛选出的化合物进行分子对接，以对接模型蛋白结构。从结合能最高的化合物中提取出顶级命中化合物。在 1 个结合位点上，ZINC3830554 与 LYS143 形成盐桥，与 ALA8、VAL45、HIS47、SER142、ASN277、ASN359 和 TRP363 形成氢键，显示出最高的结合能-12.91kcal/mol。在 2 个结合位点上，ZINC203686879 显示出最高的结合能（-12.56 kcal/mol），与 VAL187、VAL189、HIS205、LYS301、GLN347、TRP370 形成疏水相互作用，并与 GLY300、THR302、GLN347、SER350 形成氢键。对这些命中化合物进行了蛋白-配体复合物的动力学模拟（MD）稳定性检查，并通过分子力学能量与泊松-玻尔兹曼（MM/PBSA）相结合的方法计算了结合自由能。我们希望这些命中化合物能够成为有效的抑制剂，通过阻断 TMPRSS2 的活性，降低病毒的感染力和传染性，从而阻止 SARS-CoV-2 病毒进入靶向人类细胞。
