Dear Editor.

Remdesivir is thought to be effective for certain groups of patients suffering from COVID-19 illness. Currently, FDA has approved it for the purpose and WHO has issued a conditional recommendation for its use. Some evidence has been gathered in favor of its use, but data from large scale clinical trials are expected to give more insight into the matter [1].

At the present moment, molecular understanding regarding the use of remdesivir in SARS-CoV2 infected patients (COVID-19 disease) is scanty. Remdesivir is a nucleotide analogue that inhibits RNA dependent RNA polymerase (RdRp) of the virus. In case the binding site of the drug is mutated, remdesivir may not fit in the active site for the desired effect. It is in this context, we have docked remdesivir at the binding site of wild type RdRp bound template primer RNA complex (please see supplimentary). The remdesivir was observed to fitted there with binding energy -8.68 kcal/mol. The reported interacting residues (R555, V557, D618, T680, N691, D760 and D761) are in contact with remdesivir ring and are shown in Fig. 1a [2]. The nucleoside homolog ring faces towards the primer-template implying inhibition of elongation of viral RNA.

Fig. 1
figure 1

Conformation of remdesivir in wild type (WT) and D760 mutant RdRp-DNA complex are shown. In (a), the residues of RdRp interacting with remdesivir are represented. In (b), the position of remdesivir (in cyan colour and designated as Mutant) in D760 mutant RdRp is shown. The actual position of remdesivir is represented in magenta colour and noted as WT

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The most negative binding energy obtained in mutant cases (R555, V557, D618, T680, N691, D760, D761) were -8.93, -8.42, -6.55, -7.65, -7.42, -8.70, -8.26, respectively. In the mutant cases, remdesivir binding is shifted from the actual elongation site. However, in R555A and D760A mutant cases, the binding energy was observed to be more negative ( 8.93 and  8.70 kcal/mol, respectively). In Fig. 1b, remdesivir binding with D760 mutant RdRp with template primer is shown.

We have observed that if any of the above-mentioned interacting residues are mutated, then remdesivir binding position is changed. So, in case of mutated RdRp, remdesivir may not stop the viral RNA elongation and the virus may acquire drug resistance. In SARS–COV2 virus, mutation near the binding sites (putative docking site of remdesivir in RdRp) is found [3]. However, it causes remdesivir resistance or not is currently unknown [4]. There are views that the remdesivir resistant strain cannot survive [5]. We believe that at the current moment it is impossible to comment with certainty that remdesivir resistant strain will cause a fatal COVID-19 disease or not and more focussed research should be dedicated in the concerned field. For stepping towards such direction, we must amplify the critical viral regions and sequence it for understanding the emergence of remdesivir resistant SARS-CoV2 strain.