Computational Insights into the Structural Basis for Reduced Hepatotoxicity of Novel Nonopioid Analgesics

Acetaminophen (ApAP) toxicity arises from the reactive intermediate N ‐acetyl‐ p ‐benzoquinone imine (NAPQI), a degradation product known to cause significant liver damage and kidney injury. This toxicity is a major concern associated with the widespread use of ApAP, a commonly used nonsteroidal anti‐inflammatory drug. To address this important issue, a series of novel nonopioid analgesic candidates with reduced toxicity have been recently reported. However, the molecular and atomic‐level mechanisms underlying their decreased toxicity remain largely unexplored. In this study, computational analyses is performed to investigate the dynamic behavior, physicochemical properties, and ligand‐receptor interactions of these new chemical entities (NCEs). The findings provide a rational explanation for their differing toxicity profiles and contribute to a deeper understanding of their metabolic pathways. Based on these insights, compound 6 has emerged as a promising ApAP alternative and is currently under development. These investigations pave the way for designing novel hepatotoxicity‐free NCE analgesics with improved drug metabolism and pharmacokinetic properties.