Structure‐Based Design and Synthesis of Highly Potent SARS‐CoV 3CL Protease Inhibitors

In a successful example of lead optimization by computer modeling prediction, computational technology was used to optimize a lead inhibitor (TL-3) of the SARS-CoV 3CL protease. A novel C2-symmetric diol (1) was then designed and synthesized, and displayed higher affinity than the original lead compound by one order of magnitude in its inhibition constant (0.6→0.073 μM). We believe that this approach has provided a platform for further lead optimization.