Abstract
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.