Severe Acute Respiratory Syndrome (SARS)，嚴重急性呼吸道症狀，2003年四月起已在台灣造成許多病患感染及傷亡之快速流行的傳染病。截至目前為止尚未獲得具療效之藥物上市。由 SARS-CoV 之基因體發現了六個主要的蛋白：S (spike protein), Polymerase, M (membrane protein), N (nucleocapsid protein ), E (envelope protein), and 3CLpro (3C-like protease or Mpro)。而其中3CLpro 蛋白酶可將一具功能之polypeptide切割斷裂後使 SARS-CoV 病毒趨於成熟。由於此蛋白在病毒複製之過程中扮演一重要的角色，因此可視為具潛力發展為抗SARS新藥之標靶蛋白。以SARS-CoV 3CL蛋白酶為基礎對Maybridge化合物資進行電腦模擬篩選，實驗結果發現經由分子對接 (Docking) 59,363化合物，從中挑選出93個化合物，進行對SARS-CoV 3CL pro複製抑制之生物試驗，實驗結果顯示命中21個活性化合物，活性範圍為 IC50= 6 μM ~ 32 μM。我們繼續尋找從21活性化合物為出發點，尋找MAYBRIDGE、CHEMBRIDGE和SPEC_SC化合物資料庫，陸續找到92個衍生物，並且77個有活性，總計98個有活性。其中有28活性化合物具有相同的主架構，活性範圍為 IC50 = 3μM ~ 1000 μM。
最後，我們以配位體為基礎 (ligand-based) 探討28個先導化合物的結構與活性關係。透過3D-QSAR的工具，包含CoMFA (Comparative Molecular Field Analysis)、CoMSIA (comparative molecular similarity indices analysis) 和藥效基團 (pharmacophore)分析，將會輔助前導化合物最佳化過程 (lead optimization procedure)，以獲得最具潛力之抗 SARS 藥物。

Severe Acute Respiratory Syndrome (SARS), an epidemic sprout rapidly in Taiwan, was caused by a newly discovered coronavirus which has aroused severe illness and death since April 2003. Until now, there is no efficacious therapy available. The genome of SARS-CoV (SARS coronavirus) contains six key proteins: S (spike protein), Polymerase, M (membrane protein), N (nucleocapsid protein), E (envelope protein), and 3CLpro (3C-like protease or Mpro). Among these six proteins, 3CLpro cleaves a functional polypeptide and consequently leads to the maturation of SARS-CoV. Since its critical role in virus replication cycle, this protein becomes an attractive target to develop some anti-SARS drugs. Maybridge database was screened by a structure-based virtual screening approach based on the SARS-CoV 3CLpro. It has been found that of the 59,363 compounds docked, further tested by inhibition assay of SARS-CoV replication. 21 (IC50 = 6μM~32μM) were active out of 93. We continued to search MAYBRIDGE , CHEMBRIDGE and SPCE_SC Databases from our 21 active compounds, and found 92 derivative. Out of 92, 77 were active. Then from total 98 active compounds, we identified 28 compounds (IC50 = 3μM ~ 1000μM) with similar structure to be our lead compound.
Finally, the ligand-based would be applied as a complementary approach for studying the structure activity relationship for these 28 lead compounds found. Some advanced 3D-QSAR techniques, including CoMFA (Comparative Molecular Field Analysis) , CoMSIA (comparative molecular similarity indices analysis) and pharmacophore , will then be employed to facilitate the lead optimization procedure to obtain compounds with more potency against SARS-CoV.

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