In Silico Exploration of the Molecular Mechanism of Clinically Oriented Drugs for Possibly Inhibiting SARS-CoV-2's Main Protease.
- 作者列表："Huynh T","Wang H","Luan B
:Currently, the new coronavirus disease 2019 (COVID-19) is a global pandemic without any well-calibrated treatment. To inactivate the SARS-CoV-2 virus that causes COVID-19, the main protease (Mpro) that performs key biological functions in the virus has been the focus of extensive studies. With the fast-response experimental efforts, the crystal structures of Mpro of the SARS-CoV-2 virus have just become available recently. Herein, we theoretically investigated the mechanism of binding between the Mpro's pocket and various marketed drug molecules being tested in clinics to fight COVID-19 that show promising outcomes. By combining the existing experimental results with our computational ones, we revealed an important ligand binding mechanism of the Mpro, demonstrating that the binding stability of a ligand inside the Mpro pocket can be significantly improved if part of the ligand occupies its so-called "anchor" site. Along with the highly potent drugs and/or molecules (such as nelfinavir) revealed in this study, the newly discovered binding mechanism paves the way for further optimizations and designs of Mpro's inhibitors with a high binding affinity.
目前，新的冠状病毒疾病 2019 (新型冠状病毒肺炎) 是一个全球性的大流行，没有任何经过严格规范的治疗。为了灭活引起SARS-CoV-2 的新型冠状病毒肺炎病毒，在病毒中发挥关键生物学功能的主要蛋白酶 (Mpro) 一直是广泛研究的焦点。随着快速反应实验的努力，SARS-CoV-2 病毒Mpro的晶体结构刚刚问世。在此，我们从理论上研究了Mpro's pocket与临床测试的各种上市药物分子之间的结合机制，以对抗显示出有希望结果的新型冠状病毒肺炎。通过将现有的实验结果与我们的计算结果相结合，我们揭示了Mpro的重要配体结合机制，证明如果配体的一部分占据其所谓的 “锚” 位点，则Mpro口袋内配体的结合稳定性可以显著提高。随着本研究揭示的高效药物和/或分子 (如奈非那韦)，新发现的结合机制为进一步优化和设计具有高结合亲和力的Mpro抑制剂铺平了道路。
METHODS::Since mid-December of 2019, coronavirus disease 2019 (COVID-19) infection has been spreading from Wuhan, China. The confirmed COVID-19 patients in South Korea are those who came from or visited China. As secondary transmissions have occurred and the speed of transmission is accelerating, there are rising concerns about community infections. The 54-year old male is the third patient diagnosed with COVID-19 infection in Korea. He is a worker for a clothing business and had mild respiratory symptoms and intermittent fever in the beginning of hospitalization, and pneumonia symptoms on chest computerized tomography scan on day 6 of admission. This patient caused one case of secondary transmission and three cases of tertiary transmission. Hereby, we report the clinical findings of the index patient who was the first to cause tertiary transmission outside China. Interestingly, after lopinavir/ritonavir (Kaletra, AbbVie) was administered, β-coronavirus viral loads significantly decreased and no or little coronavirus titers were observed.
METHODS::In December 2019, a novel coronavirus (2019-nCoV) caused an outbreak in Wuhan, China, and soon spread to other parts of the world. It was believed that 2019-nCoV was transmitted through respiratory tract and then induced pneumonia, thus molecular diagnosis based on oral swabs was used for confirmation of this disease. Likewise, patient will be released upon two times of negative detection from oral swabs. However, many coronaviruses can also be transmitted through oral-fecal route by infecting intestines. Whether 2019-nCoV infected patients also carry virus in other organs like intestine need to be tested. We conducted investigation on patients in a local hospital who were infected with this virus. We found the presence of 2019-nCoV in anal swabs and blood as well, and more anal swab positives than oral swab positives in a later stage of infection, suggesting shedding and thereby transmitted through oral-fecal route. We also showed serology test can improve detection positive rate thus should be used in future epidemiology. Our report provides a cautionary warning that 2019-nCoV may be shed through multiple routes.
METHODS::There is a current worldwide outbreak of a new type of coronavirus (2019-nCoV), which originated from Wuhan in China and has now spread to 17 other countries. Governments are under increased pressure to stop the outbreak spiraling into a global health emergency. At this stage, preparedness, transparency, and sharing of information are crucial to risk assessments and beginning outbreak control activities. This information should include reports from outbreak sites and from laboratories supporting the investigation. This paper aggregates and consolidates the virology, epidemiology, clinical management strategies from both English and Chinese literature, official news channels, and other official government documents. In addition, by fitting the number of infections with a single-term exponential model, we report that the infection is spreading at an exponential rate, with a doubling period of 1.8 days.