论文标题
4487类黄酮的高通量虚拟筛查：关于SARS-COV-2主要蛋白酶结构抑制的新见解
High-Throughput Virtual Screening of 4487 flavonoids: New insights on the structural inhibition of SARS-CoV-2 Main Protease
论文作者
论文摘要
COVID-19对全球公共卫生构成了巨大威胁，感染力的SARS-COV-2目前是针对抑制作用的大量研究的目标。病毒的主要蛋白酶是一种二聚体酶，直到最近才开始彻底描述，为虚拟筛查打开了大门。在这里，对蛋白酶的四个位点进行了筛选疼痛过滤的类黄酮数据库：底物结合位点（NSB）的自由（正常）构象，SBS（ISBS）的诱导拟合状态，二聚体位点（DS）（DS）和一个隐性位点（CS）。对于NSB，ISB，DS和CS，每个位点前五个配体的平均结合能分别为-9.52，-11.512，-7.042和-10.348 kcal/mol。对于DS和CS，选择了这些前五种化合物作为候选者来绑定其各自位点。对于SBS，将来自NSB和ISB的最低结合能的前30个配体对比，并且两个列表中存在的配体被选为最终候选者。最终列表是：背膜蛋白E（FL3FQUNP0001），Euchrenone A11（FL2FALNP0014），Kurziflavolactone C（FL2FA9NC0016），甘草甘油糖苷E（FL2F1AGSN001）和3'--苯基 - 二烯基 - 二氧化物（FL2F1AGSN001）（FL2F1AGSN001）（FL2F1AGSN001）对于SBS; sanggenol O（FL2FALNP0020），Chembl2171573，Kanzonol E（FL3F1ANP0001），Chembl2171584和Abyssynoflavanone VI（FL2FACNP0014） （FL5FAANR0001），kurzichalcolactone（FL1CA9NC0001）和Chembl2171578用于CS。
COVID-19 presents a great threat to public health worldwide and the infectious agent SARS-CoV-2 is currently the target of much research aiming at inhibition. The virus' main protease is a dimeric enzyme that has only recently begun to be thoroughly described, opening the door for virtual screening more broadly. Here, a PAIN-filtered flavonoid database was screened against four sites of the protease: a free (normal) conformation of the Substrate Binding Site (NSBS), an induced-fit state of the SBS (ISBS), a Dimerization Site (DS) and a Cryptic Site (CS). The mean binding energies of the top five ligands from each site were -9.52, -11.512, -7.042 and -10.348 kcal/mol for the NSBS, the ISBS, the DS and the CS, respectively. For the DS and CS, these top five compounds were selected as candidates to bind their respective site. In the case of SBS, the top 30 ligands with the lowest binding energies from NSBS and ISBS were contrasted and the ones present in both lists were selected as the final candidates. The final list was: Dorsilurin E (FL3FQUNP0001), Euchrenone a11 (FL2FALNP0014), Kurziflavolactone C (FL2FA9NC0016), Licorice glycoside E (FL2F1AGSN001) and Taxifolin 3'- (6"-phenyl- acetylglucoside) (FL4DACGS0020) for the SBS; Sanggenol O (FL2FALNP0020), CHEMBL2171573, Kanzonol E (FL3F1ANP0001), CHEMBL2171584 and Abyssynoflavanone VI (FL2FACNP0014) for DS and CHEMBL2171598, CHEMBL2171577, Denticulaflavanol (FL5FAANR0001), Kurzichalcolactone (FL1CA9NC0001) and CHEMBL2171578 for CS. Virtual screening integrated several confirmation methods, including cross-docking assays and positive and negative controls. All 15 compounds are currently subjected to molecular dynamics so as to theoretically validate their binding to the protease.
