Severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (M pro ), a protein required for the maturation of SARS-CoV, is vital for its life cycle, making it an attractive target for structure-based drug design of anti-SARS drugs. The structure-based virtual screening of a chemical database containing 58 855 compounds followed by the testing of potential compounds for SARS-CoV M pro inhibition leads to two hit compounds. The core structures of these two hits, defined by the docking study, are used for further analogue search. Twenty-one analogues derived from these two hits exhibited IC 50 values below 50 µM, with the most potent one showing 0.3 µM. Furthermore, the complex structures of two potent inhibitors with SARS-CoV M pro were solved by X-ray crystallography. They bind to the protein in a distinct manner compared to all published SARS-CoV M pro complex structures. They inhibit SARS-CoV M pro activity via intensive H-bond network and hydrophobic interactions, without the formation of a covalent bond. Interestingly, the most potent inhibitor induces protein conformational changes, and the inhibition mechanisms, particularly the disruption of catalytic dyad (His41 and Cys145), are elaborated.

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