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

Abstract

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.