When Side Effects Become Therapies: A Mechanistic Taxonomy of Adverse Drug Reactions as Translational Signals for Drug Repositioning
Abstract
Background: The systematic conversion of adverse drug reactions (ADRs) into new therapeutic indications represents one of the oldest and most productive sources of repositioned drugs; however, it has not been subjected to formal mechanistic analysis.
Objectives: This study aims to propose a mechanistic taxonomy of convertible ADRs and a structured workflow for translating documented adverse effects into testable repositioning hypotheses.
Methods: In this narrative review, historical cases of ADR-driven repositioning spanning five decades-from sildenafil and minoxidil to semaglutide-were analyzed and classified within a four-dimensional framework organized along the axes of: (1) target identity (on-target versus off-target conversion); (2) dose, route of administration, and reformulation; (3) patient population and clinical context; and (4) pharmacogenomic variability.
Results: Each historical case was successfully classified within the proposed taxonomy. A five-step theoretical workflow-comprising signal identification, taxonomic classification, mechanistic verification, feasibility assessment, and preliminary evidence search-was developed to operationalize the framework for prospective hypothesis generation. Computational tools including side-effect similarity networks, network pharmacology, and transcriptomic signature reversal were identified as means to support specific workflow steps.
Conclusions: The proposed taxonomy and workflow provide a replicable,…
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