Structural analysis of inhibition mechanisms of Aurintricarboxylic Acid on SARS-CoV polymerase and other proteins

We recently published experimental results that indicated Aurintricarboxylic Acid (ATA) could selectively inhibit SARS-CoV replication inside host cells by greater than 1000 times. This inhibition suggested that ATA could be developed as potent anti-viral drug. Here, to extend our experimental observation, we have incorporated protein structural studies (with positive/negative controls) to investigate the potential binding modes/sites of ATA onto RNA-dependent RNA polymerase (RdRp) from SARS-CoV and other pathogenic positive-strand RNA-viruses, as well as other proteins in SARS-CoV based on the fact that ATA binds to Ca2+-activated neutral protease (m-calpain), the protein tyrosine phosphatase (PTP) and HIV integrase which have existing crystal structures. Eight regions with homologous 3D-conformation were derived for 10 proteins of interest. One of the region, Rbinding (754-766 in SARS-CoV's RdRp), located in the palm sub-domain mainly constituted of anti-parallel β-strand-turn-β-strand hairpin structures that covers two of the three RdRp catalytic sites (Asp 760, Asp761), was also predicted by molecular docking method (based on free energy of binding ΔG) to be important binding motif recognized by ATA. The existence of this strictly conserved region that incorporated catalytic residues, coupled with the homologous ATA binding pockets and their consistent ΔG values, suggested strongly ATA may be involved in an analogous inhibition mechanism of SARS-COV's RdRp in concomitant to the case in m-calpain, PTP and HIV integrase.