Virtual screening identification of novel severe acute respiratory syndrome 3C-like protease inhibitors and in vitro confirmation

Abstract

The 3C-like protease (3CL(pro)) of severe acute respiratory syndrome associated coronavirus (SARS-CoV) is vital for SARS-CoV replication and is a promising drug target. Structure based virtual screening of 308307 chemical compounds was performed using the computation tool Autodock 3.0.5 on a WISDOM Production Environment. The top 1468 ranked compounds with free binding energy ranging from -14.0 to -17.09 kcal mol(-1) were selected to check the hydrogen bond interaction with amino acid residues in the active site of 3CL(pro). Fifty-three compounds from 35 main groups were tested in an in vitro assay for inhibition of 3CL(pro) expressed by Escherichia coli. Seven of the 53 compounds were selected; their IC(50) ranged from 38.57±2.41 to 101.38±3.27 μM. Two strong 3CL(pro) inhibitors were further identified as competitive inhibitors of 3CL(pro) with K(i) values of 9.11±1.6 and 9.93±0.44 μM. Hydrophobic and hydrogen bond interactions of compound with amino acid residues in the active site of 3CL(pro) were also identified.

Structural Insight Into the Viral 3C-Like Protease Inhibitors: Comparative SAR/QSAR Approaches

“…Compounds 3 and 9 exhibited the aberrant behavior and thus were considered as outliers. Nguyen et al (2011) reported some promising SARS-CoV 3CL pro inhibitors through virtual screening ( Fig. 11.9; Table 11.22).…”

In silico virtual screening approaches for anti-viral drug discovery

“…In a study published in 2011, Ngoyen et al describe a VS workflow by which two compounds with inhibitory activity against SARS-CoV 3CL pro at low micromolar concentrations could be identified [52]. To achieve this, a commercial compound database was screened in a procedure involving (i) filtering by predicted toxical properties, (ii) docking, (iii) filtering by free energy calculation and potential H-bond formation between the protein and the ligand, and (iv) a clustering and visual inspection step.…”

How Prepared Are We to Control Severe Acute Respiratory Syndrome in Future

“…Besides, several groups have identified a number of inhibitors of 3CLpro using a variety of approaches. Virtual screening (Plewczynski et al, 2007;Mukherjee et al, 2008;Nguyen et al, 2011) or a high-throughput screening of small molecule libraries have identified inhibitorsincluding an anti-HIV agent and serotonin antagonist, cinanserin (Blanchard et al, 2004;Kao et al, 2004;Wu et al, 2004a;Chen et al, 2005). Other 3CL protease inhibitors identified so far belongto categories such as plant derived phenolic or flavonoid compounds (Lin et al, 2005;Nguyen et al, 2012), active site, nonactive site or competitive inhibitors (Kaeppler et al, 2005;Lee et al, 2005;Du et al, 2007;Ryu et al, 2010), ketones or ester based inhibitors (Goetz et al, 2007;Zhang et al, 2007;Ghosh et al, 2008;Shao et al, 2008;Verschueren et al, 2008;Zhang et al, 2008), modified peptidomimetic inhibitors (Ghosh et al, 2007), metal conjugated inhibitors (Lee et al, 2007;…”