Comparative Evidence-Weighted In Silico Toxicity Profiling of the SARS-CoV-2 Main Protease Inhibitors Ensitrelvir and Nirmatrelvir

Ensitrelvir and nirmatrelvir are the two most widely used oral SARS-CoV-2 main protease inhibitors, yet their toxicological profiles have never been compared under a single computational panel. An identical panel of 105 toxicity endpoints per compound was generated with ADMETlab 3.0, ProTox 3.0, Deep-PK, admetSAR 3.0 and Pred-hERG 5.0, yielding 210 endpoint-level predictions across 17 toxicological domains. Each endpoint formed a matched pair classified as shared positive, shared negative, discriminant or crossed, and predictions were compared against primary clinical and nonclinical literature under a three-level admissibility hierarchy that excluded prescribing information, regulatory review documents and commercial databases. Of 93 class-assignable pairs, 73 assigned both to the same class, 62 negative, and 20 differed. Four domains were shared positive: genotoxicity, with broad genotoxicity and micronucleus probabilities of 1.000 for both molecules, respiratory toxicity, nephrotoxicity and neurotoxicity; ototoxicity was high for both in a single tool. The largest separation was hepatic: ensitrelvir returned drug-induced liver injury 1.000 and human hepatotoxicity 0.994, against 0.314 and 0.456 for nirmatrelvir. Target class therefore does not determine predicted toxicological profile. Genotoxicity, respiratory, renal and neural endpoints are class-level validation priorities, whereas hepatic and hERG endpoints require compound-specific testing. These findings are hypothesis-generating prioritization markers, not confirmed toxicity.