A 3D model of SARS_CoV 3CL proteinase and its inhibitors design by virtual screening

AIM: To constructed a three-dimensional (3D) model for the 3C like (3CL) proteinase of SARS coronavirus (SARS_CoV), and to design inhibitors of the 3CL proteinase based on the 3D model. METHODS: Bioinformatics analyses were performed to search the homologous proteins of the SARS_CoV 3CL proteinase from the GenBank and PDB database. A 3D model of the proteinase was constructed by using homology modeling technique. Targeting to the 3D model and its X-ray crystal structure of the main proteinase (M^pro) of transmissible gastroenteritis virus (TGEV), virtual screening was performed employing molecular docking method to identify possible 3CL proteinase inhibitors from small molecular databases. RESULTS: Sequence alignment indicated that the SARS_CoV 3CL proteinase was extremely homologous to TGEV M^pro, especially the substrate-binding pocket (active site). Accordingly, a 3D model for the SARS_CoV 3CL proteinase was constructed based on the crystal structure of TGEV M^pro. The 3D model adopts a similar fold of the TGEV M^pro, its structure and binding pocket feature are almost as same as that of TGEV M^pro. The tested virtual screening indicated that 73 available proteinase inhibitors in the MDDR database might dock into both the binding pockets of the TGEV M^pro and the SARS_CoV 3CL proteinase. CONCLUSIONS: Either the 3D model of the SARS_CoV 3CL proteinase or the X-ray crystal structure of the TGEV M^pro may be used as a starting point for design anti-SARS drugs. Screening the known proteinase inhibitors may be an appreciated shortcut to discover anti-SARS drugs.