Structural basis of mercury- and zinc-conjugated complexes as SARS-CoV 3C-like protease inhibitors

Five active metal-conjugated inhibitors (PMA, TDT, EPDTC, JMF1586 and JMF1600) bound with the 3C-like protease of severe acute respiratory syndrome (SARS)-associated coronavirus were analyzed crystallographically. The complex structures reveal two major inhibition modes: Hg2+-PMA is coordinated to C44, M49 and Y54 with a square planar geometry at the S3 pocket, whereas each Zn2+ of the four zinc-inhibitors is tetrahedrally coordinated to the H41-C145 catalytic dyad. For anti-SARS drug design, this Zn2+-centered coordination pattern would serve as a starting platform for inhibitor optimization.