目的 運(yùn)用分子對(duì)接技術(shù)模擬預(yù)測(cè)TCMSP數(shù)據(jù)庫(kù)中藥成分對(duì)新型冠狀病毒（SARS-CoV-2）3CL水解酶的作用。方法 基于SARS-CoV-2 3CL水解酶的PDB晶型結(jié)構(gòu)（6LU7），構(gòu)建虛擬靶標(biāo)模型，以TCMSP數(shù)據(jù)庫(kù)中的13 143個(gè)化合物為配體篩選對(duì)象，以6LU7原配體分子為對(duì)照，采用薛定諤2018軟件，以Glide程序建立6LU7分子對(duì)接體系。然后以原配體分子的對(duì)接打分結(jié)果為閾值，口服生物利用度（OB）≥30%或類藥性（DL）≥0.18為標(biāo)準(zhǔn)篩選候選化合物。最后建立“成分-藥材-歸經(jīng)-功效”網(wǎng)絡(luò)，對(duì)候選成分的主要藥材歸屬和作用功效進(jìn)行總結(jié)。結(jié)果 按照對(duì)接打分、OB、DL篩選標(biāo)準(zhǔn)，共篩選得到60個(gè)化合物。受體-配體相互作用結(jié)果顯示，候選化合物主要與靶點(diǎn)蛋白的GLU166、GLY143、ASP187、CYS145、GLN189和LEU141等發(fā)生氫鍵作用。網(wǎng)絡(luò)預(yù)測(cè)結(jié)果顯示，所篩選化合物主要?dú)w屬藥材為甘草、桑白皮、滿山紅、虎杖和車前草等，肺臟是作用的關(guān)鍵靶器官，其作用功效以清熱解毒、止咳祛痰、瀉肺平喘等為主。結(jié)論 對(duì)TCMSP數(shù)據(jù)庫(kù)化合物進(jìn)行虛擬分子對(duì)接得到的結(jié)果為SARS-CoV-2 3CL水解酶抑制劑篩選提供了相關(guān)數(shù)據(jù)。

Objective To identify potential SARS-CoV-2 3CL protease inhibitors from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) by molecular docking approach. Methods To alternate extensive compounds experimental screening processes, a Computer-Aided Drug Design (CADD) based molecular docking technology was performed to explore existing drug repurposing possibilities. Molecular docking model with Schrodinger suit 2018 was used to evaluate the binding abilities between TCMSP 13 143 compounds and SARS-CoV-2 3CL protease receptor-binding domain (PBD ID 6LU7), which involving in mediating viral replication and transcription functions. According to the constructed docking system, potential compounds were screened according to docking score, oral bioavailability (OB), and drug-likeness (DL). At last, a compounds-herb-target organ-function network was constructed. Results Compared with 6LU7 original ligand docking score (-7.734), a total of 498 compounds were identified with lower docking score against 6LU7 targets. These compounds were further reduced to 60 high-priority compounds, based on OB (more than 30) and DL (more than 0.18). Meanwhile, these 60 compounds were found to interact with the amino acid residues (GLU166, GLY143, ASP187, CYS145, GLN189, LEU141, etc.) which were critically involved in the 6LU7 domain mainly by hydrogen-bonded interaction. The network exploring results revealed that these potential compounds were mainly attributed to Glycyrrhizae Radix et Rhizoma, Mori Cortex, Rhododendron dauricum, Polygoni Cuspidati Rhizoma et Radix, and Plantaginis Herba, etc., which associates with acute lung syndromes induced by SARS-CoV-2, with the effect of clearing heat and removing toxin, relieving cough and dispelling phlegm and lung-draining and relieving asthma. Conclusion Molecular docking method provides a useful tool for the screening of SARS-CoV-2 3CL protease inhibitors from TCMSP platform.

R285.5

2020年度咸陽(yáng)市重點(diǎn)研發(fā)計(jì)劃“新型冠狀病毒肺炎疫情應(yīng)急防治”科技專項(xiàng)；陜西省三秦學(xué)者創(chuàng)新團(tuán)隊(duì)；陜西省“特支計(jì)劃”青年拔尖人才項(xiàng)目（陜組通字[2018]33號(hào)）