Abstract
In the present study we tested, using the microscale thermophoresis technique, a small library of thionocarbamates, thiolocarbamates, sulfide and disulfide as potential lead compounds for SARS-CoV-2 Mpro drug design. The successfully identified binder is a representative of the thionocarbamates group with a high potential for future modifications aiming for higher affinity and solubility. The experimental analysis was extended by computational studies that show insufficient accuracy of the simplest and widely applied approaches and underline the necessity of applying more advanced methods to properly evaluate the affinity of potential SARS-CoV-2 Mpro binders.
Highlights
The highly conserved region in the Mpro, the substrate-binding pocket, gives rise to a hope that compounds that inhibit the analogous protein in SARS-CoV-1 could work on SARS-CoV-2 and provide a fast cure, for the treatment of the COVID-19 patients [1]
We found that dockcalculations show, theto thionocarbamate compound is capable form an additional ing procedures arethat unable reproduce the binding affinity, but theto hydrogen bond andthat thusthe stabilize its positioncompound in the Mpro site, the correcalculations show, thionocarbamate is active capable to whereas form an additional sponding thiolocarbamate tends to leave the active site
We tested a small group of activesimple site, such as the SARS-CoV2-Mpro
Summary
The highly conserved region in the Mpro, the substrate-binding pocket, gives rise to a hope that compounds that inhibit the analogous protein in SARS-CoV-1 could work on SARS-CoV-2 and provide a fast cure, for the treatment of the COVID-19 patients [1]. Previous computational studies have shown that such a strategy can be insufficient [2,3]. The initial attempts of known inhibitors repositioning have failed and none of the previously discovered compounds were applied in treatment [4,5,6,7]. The fluorescence resonance energy transfer technique was used to test thiophene-2carboxylate derivatives, quinoline derivatives, quercetins, peptidomimetics, anilides and others on the SARS-CoV2 Mpro [16]. Several groups have used a high-throughput X-ray crystallographic screening of drug libraries or small fragments against the SARS-CoV2Mpro [17]
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