Key result
Sofosbuvir derivatives match the parent drug for SARS-CoV-2 RdRp binding affinity in silico.
Why the study?
Emerging resistant variants of SARS-CoV-2 pose an ongoing threat, and targeting viral RNA-dependent RNA polymerase with modified inhibitors is needed to prevent replication.
Absolute Event Rate: -16.28% vs -16.2%
In silico modeling identifies sofosbuvir derivatives (compounds 3 and 4) as potential SARS-CoV-2 RdRp blockers with binding affinities comparable to the parent drug.
Hypothesis-generating for sofosbuvir derivatives as RdRp inhibitors; requires in vitro and in vivo validation before any clinical consideration.
The human coronavirus, SARS-CoV-2, had a negative impact on both the economy and human health, and the emerging resistant variants are an ongoing threat. One essential protein to target to prevent virus replication is the viral RNA-dependent RNA polymerase (RdRp). Sofosbuvir, a uridine nucleotide analog that potently inhibits viral polymerase, has been found to help treat SARS-CoV-2 patients. This work combines molecular docking and dynamics simulation (MDS) to test 14 sofosbuvir-based modifications against SARS-CoV-2 RdRp. The results reveal comparable (slightly better) average binding affinity of five modifications (compounds 3, 4, 11, 12, and 14) to the parent molecule, sofosbuvir. Compounds 3 and 4 show the best average binding affinities against SARS-CoV-2 RdRp (- 16.28 ± 5.69 and - 16.25 ± 5.78 kcal/mol average binding energy compared to - 16.20 ± 6.35 kcal/mol for sofosbuvir) calculated by Molecular Mechanics Generalized Born Surface Area (MM-GBSA) after MDS. The present study proposes compounds 3 and 4 as potential SARS-CoV-2 RdRp blockers, although this has yet to be proven experimentally.
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Alrehaily et al. (2023) studied SARS-CoV-2. Sofosbuvir derivatives (compounds 3 and 4) vs. Sofosbuvir was evaluated on Average binding affinity to SARS-CoV-2 RdRp (kcal/mol). In silico molecular dynamics simulations demonstrated that sofosbuvir derivatives, specifically compounds 3 and 4, exhibited comparable binding affinities to SARS-CoV-2 RdRp as the parent drug sofosbuvir.
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