In Silico Evaluation of Structural Consequences in the Human CYP3A4 Caused by Molnupiravir-Induced Mutations During COVID-19 Treatment
et al., Drugs and Drug Candidates, doi:10.3390/ddc4040050, Nov 2025
In silico study showing potential harm from molnupiravir-induced mutations in human CYP3A4 enzyme during COVID-19 treatment. Authors identified six hotspot amino acids (R105, W126, R130, R375, S437, R440) in the CYP3A4 active site that could be mutated by molnupiravir, with mutations at positions 105, 126, and 130 causing premature stop codons resulting in severely truncated, non-functional enzyme variants. The study suggests that molnupiravir-induced mutations could impair CYP3A4 function, potentially leading to inefficient drug metabolism and accumulation of medications in COVID-19 patients with comorbidities, particularly affecting the efficacy of paxlovid treatment where ritonavir relies on CYP3A4 inhibition to boost nirmatrelvir levels.
Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-15. Multiple analyses have identified variants potentially created by molnupiravir16-20. Studies show significantly increased risk of acute kidney injury21, cardiovascular toxocity22, and neurological symptoms21. Treatment may increase viral rebound23,24.
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Aggunna et al., 11 Nov 2025, India, peer-reviewed, 11 authors.
Contact: tcabse.india@gmail.com (corresponding author), aggunnamadhumita@gmail.com, gantetichiranjeevi42@gmail.com, keerthirathod91@gmail.com, minnimeghana2@gmail.com, joyjethinneelam@gmail.com, aswithagurrala@gmail.com, grandhibavana@gmail.com, noahjeevanvejendla@gmail.com, kruparabbuni@gmail.com.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
In Silico Evaluation of Structural Consequences in the Human CYP3A4 Caused by Molnupiravir-Induced Mutations During COVID-19 Treatment
Drugs and Drug Candidates, doi:10.3390/ddc4040050
Background/Objectives: Molnupiravir (MOV) and nirmatrelvir (NMV) are antiviral drugs that were FDA-approved under the emergency use authorization (EUA) for coronavirus disease-2019 (COVID-19) treatment. MOV and NMV target the viral RNA-dependent RNA polymerase and main protease, respectively. Paxlovid is a combination of NMV and ritonavir (RTV), an inhibitor of the human cytochrome P450-3A4 (hCYP3A4). In this study, the structural consequences in the hCYP3A4 caused by MOV-induced mutations (MIM) were evaluated using in silico tools. Methods: MOV-induced mutations (MIM) were inserted into all the possible hotspots in the active site region of the hCYP3A4 gene, and mutant protein models were built. Structural changes in the heme-porphyrin ring of hCYP3A4 were analyzed in the presence and absence of substrates/inhibitors, including RTV. Molecular dynamics (MD) simulations were performed to analyze the effect of MIMinduced structural changes in hCYP3A4 on drug binding. Results: MD simulations confirm that MIMs, R375G and R440G in hCYP3A4 severely affect the heme-porphyrin ring stability by causing a tilt that in turn affects RTV binding, suggesting a possible inefficiency in the function of hCYP3A4. Similar results were seen for amlodipine, atorvastatin, sildenafil and warfarin, which are substrates of hCYP3A4. Conclusions: The current in silico studies indicate that hCYP3A4 containing MIMs can create complications in the treatment of COVID-19 patients, particularly with co-morbidities due to its functional inefficiency. Hence, clinicians must be vigilant when using MOV in combination with other drugs. Further in vitro studies focused on hCYP3A4 containing MIMs are currently in progress to support our current in silico findings.
Author Contributions: M.A., A.G., B.G., J.N., M.M., N.V. and S.M. generated all the mutant models of hCYP3A4 with MIMs, analyzed them by MD simulations and plotted the trajectory data for hCYP3A4; C.V.M.G. and K.R.B. performed docking and MD simulations of hCYP3A4 ligands; S.G. co-supervised A.G., B.G., J.N., M.M., N.V. and S.M.; R.S.Y. is the principal investigator who designed the study and supervised M.A., C.V.M.G., K.R.B., A.G., B.G., J.N., M.M., N.V. and S.M.; R.S.Y. is responsible for project administration, funding acquisition, conceptualization, writing, editing and finalizing the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding.
Conflicts of Interest: The authors in this manuscript declare no conflicts of interest.
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