目的 探討以跨膜絲氨酸蛋白酶2（TMPRSS2）為受體的單體化合物治療新型冠狀病毒肺炎（COVID-19）的作用機制。方法 借助BindingDB數(shù)據(jù)庫檢索作用于TMPRSS2受體的單體化合物。通過UniProt、GeneCards等數(shù)據(jù)庫查詢單體化合物作用靶點對應(yīng)的基因名，進而運用Cytoscape 3.2.1構(gòu)建化合物-靶點（基因）網(wǎng)絡(luò)，通過WebGestalt數(shù)據(jù)庫進行GO功能注釋和Pathway通路分析，預(yù)測其作用機制。運用SWISS-MODEL進行TMPRSS2蛋白質(zhì)三級結(jié)構(gòu)預(yù)測，利用AutoDock軟件進行化合物與TMPRSS2受體的分子對接。結(jié)果 通過BindingDB數(shù)據(jù)庫發(fā)現(xiàn)3個作用于TMPRSS2的單體化合物：（2S）-1[（（-2R）-2（-芐基磺?；被?5（-二氨基亞甲基氨基）戊酰基]-N[（-4-氨基甲?；交┘谆鵠吡咯烷-2-羧酰胺（CID-46899577，分子式C₂₆H₃₆N₈O₄S）、4[[[（（-5R）-5（-芐磺?；被?8（-二氨基甲基亞氨基）氨基-4-氧代辛烷-3-基]氨基]甲基]苯羧酰亞胺（CID-56677007，分子式C₂₄H₃₅N₇O₃S）、4[[[（（-4_S，6_R）-6（-芐基磺?；被?9（-二氨基亞甲基氨基）-5-氧肟酮-4-基]氨基]甲基]苯羧酰亞胺（CID-56663319，分子式C₂₅H₃₇N₇O₃S）；單體化合物-靶點網(wǎng)絡(luò)中靶點58個，GO功能富集分析得到GO條目380個（P<0.05），其中生物過程（BP）條目310個，細(xì)胞組成（CC）條目14個，分子功能（MF）條目56個。KEGG通路富集篩選得到26條信號通路，涉及干擾素-γ信號傳導(dǎo)途徑、轉(zhuǎn)化生長因子-β（TGF-β）信號通路、白介素信號通路等。分子對接結(jié)果顯示，TMPRSS2與C₂₆H₃₆N₈O₄S、C₂₄H₃₅N₇O₃S及甲磺酸卡莫司他都能自發(fā)結(jié)合，且2種化合物與甲磺酸卡莫司他結(jié)合能相近。結(jié)論 單體化合物C₂₆H₃₆N₈O₄S、C₂₄H₃₅N₇O₃S與TMPRSS2能自發(fā)結(jié)合，作用于F2、PLG、PLAU、PLAT、HSP90AA1、XIAP、AKT1、AKT2、AKT3等靶點調(diào)節(jié)多條信號通路，有可能對COVID-19有治療作用。

Objective To explore the mechanism of monomeric treatment of corona virus disease 2019 (COVID-19) by using transmembrane serine protease 2 (TMPRSS2) as a receptor. Methods The monomer compounds acting on the TMPRSS2 receptor were searched by the BindingDB database. Use UniProt, GeneCards and other databases to query the gene name corresponding to the target of the monomer compound, and then use Cytoscape 3.2.1 to build a compound-target (gene) network. Use the WebGestalt database to perform GO function annotation and Pathway analysis to predict its mechanism. The third-order structure of TMPRSS2 protein was predicted by SWISS-MODEL, and the molecular docking between the compound and TMPRSS2 receptor was carried out by auto dock software. Results Three monomer compounds acting on TMPRSS2 were found through the BindingDB database:(2S)-1-[(2R)-2-(Benzylsulfonylamino)-5-Guanidino-Pentanoyl]-N-[(4-Carbamimidoylphenyl)methyl] pyrrolidine-2-Carboxamide (CID-46899577, Molecular formula:C₂₆H₃₆N₈O₄S), 4-[[[(5R)-5-(Benzylsulfonylamino)-8-(diaminomethylideneamino)-4-oxooctan-3-yl]amino] methyl] benzenecarboximidamide (CID-56677007, Molecular formula:C₂₄H₃₅N₇O₃S), 4-[[[(4S, 6R)-6-(Benzylsulfonylamino)-9-(diaminomethylideneamino)-5-oxononan-4-yl]amino]methyl]benzenecarboximidamide(CID-56663319, Molecular formula:C₂₅H₃₇N₇O₃S). There were 58 targets in the monomer compound-target network, and 380 GO entries were obtained by GO functional enrichment analysis (P<0.05), including 310 biological process (BP) entries, 14 cell composition (CC) entries, and molecules. There are 56 function (MF) entries. The KEGG pathway was enriched and screened to obtain 26 signaling pathways, which involved the interferon-γ signaling pathway, the TGF-beta signaling pathway, and the interleukin signaling pathway. The molecular docking results show that TMPRSS2 can spontaneously bind to the three compounds carmoselta mesylate C₂₆H₃₆N₈O₄S, and C₂₄H₃₅N₇O₃S. Conclusion Monomeric compounds C₂₆H₃₆N₈O₄S and C₂₄H₃₅N₇O₃S combined with TMPRSS2 act on targets such as F2, PLG, PLAU, PLAT, HSP90AA1, XIAP, AKT1, AKT2, and AKT3 to regulate multiple signaling pathways, which may have therapeutic effects on COVID-19.

湖南省衛(wèi)計委科研計劃課題（B20180102、B20180714）