Title : Structural Basis of the Potential Binding Mechanism of Remdesivir to SARS-CoV-2 RNA-Dependent RNA Polymerase.

Pub. Date : 2020 Aug 13

PMID : 32521159






11 Functional Relationships(s)
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1 Here, we used molecular dynamics simulations and free energy perturbation methods to study the inhibition mechanism of remdesivir to its target SARS-CoV-2 virus RNA-dependent RNA polymerase (RdRp). remdesivir ORF1a polyprotein;ORF1ab polyprotein Severe acute respiratory syndrome coronavirus 2
2 We then built a putative preinsertion binding structure by aligning the remdesivir + RdRp complex to the ATP bound poliovirus RdRp without the RNA template. remdesivir ORF1a polyprotein;ORF1ab polyprotein Severe acute respiratory syndrome coronavirus 2
3 We then built a putative preinsertion binding structure by aligning the remdesivir + RdRp complex to the ATP bound poliovirus RdRp without the RNA template. remdesivir ORF1a polyprotein;ORF1ab polyprotein Severe acute respiratory syndrome coronavirus 2
4 We then built a putative preinsertion binding structure by aligning the remdesivir + RdRp complex to the ATP bound poliovirus RdRp without the RNA template. Adenosine Triphosphate ORF1a polyprotein;ORF1ab polyprotein Severe acute respiratory syndrome coronavirus 2
5 The resulting stable preinsertion state of remdesivir appeared to form hydrogen bonds with the RNA template when aligned with the newly solved cryo-EM structure of SARS-CoV-2 RdRp. remdesivir ORF1a polyprotein;ORF1ab polyprotein Severe acute respiratory syndrome coronavirus 2
6 The relative binding free energy between remdesivir and ATP was calculated to be -2.80 +- 0.84 kcal/mol, where remdesivir bound much stronger to SARS-CoV-2 RdRp than the natural substrate ATP. remdesivir ORF1a polyprotein;ORF1ab polyprotein Severe acute respiratory syndrome coronavirus 2
7 The relative binding free energy between remdesivir and ATP was calculated to be -2.80 +- 0.84 kcal/mol, where remdesivir bound much stronger to SARS-CoV-2 RdRp than the natural substrate ATP. Adenosine Triphosphate ORF1a polyprotein;ORF1ab polyprotein Severe acute respiratory syndrome coronavirus 2
8 The relative binding free energy between remdesivir and ATP was calculated to be -2.80 +- 0.84 kcal/mol, where remdesivir bound much stronger to SARS-CoV-2 RdRp than the natural substrate ATP. remdesivir ORF1a polyprotein;ORF1ab polyprotein Severe acute respiratory syndrome coronavirus 2
9 The ~100-fold improvement in the Kd from remdesivir over ATP indicates an effective replacement of ATP in blocking of the RdRp preinsertion site. remdesivir ORF1a polyprotein;ORF1ab polyprotein Severe acute respiratory syndrome coronavirus 2
10 The ~100-fold improvement in the Kd from remdesivir over ATP indicates an effective replacement of ATP in blocking of the RdRp preinsertion site. Adenosine Triphosphate ORF1a polyprotein;ORF1ab polyprotein Severe acute respiratory syndrome coronavirus 2
11 The ~100-fold improvement in the Kd from remdesivir over ATP indicates an effective replacement of ATP in blocking of the RdRp preinsertion site. Adenosine Triphosphate ORF1a polyprotein;ORF1ab polyprotein Severe acute respiratory syndrome coronavirus 2