Exploring the pharmacological basis of adverse effects in oxazolidinone and antidepressant cotherapy: an in silico study.

Linezolid and related oxazolidinones are frontline antibiotics against multidrug-resistant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), yet their co-administration with antidepressants has been clinically associated with serotonin syndrome (SS) or hypertensive crisis (HC). While traditionally attributed to monoamine oxidase (MAO) inhibition, clinical observations remain variable and the underlying mechanism is not completely understood. In this exploratory study, we applied an integrated in silico framework combining target prediction, network similarity, and structural modeling to generate testable hypotheses regarding potential alternative targets. Consensus profiling using SwissTargetPrediction and an integrative structural- and physicochemical-based target prediction methodology predicted possible interactions of linezolid and tedizolid with MAO isoforms, alongside exploratory aminergic targets including the 5-HT1A (HTR1A) receptor and adrenergic clusters. Comparing predicted targets with clinical datasets revealed an overlap with genes associated with SS and HC. Pathway enrichment and Jaccard similarity showed notable functional convergence with sertraline (OC > 0.90). Structural comparisons and physicochemical clustering grouped oxazolidinones near neurotransmitter intermediates, such as N-acetylserotonin. Furthermore, molecular docking across multiple crystallographic structures and ligand efficiency (LE) estimations suggested theoretically favorable interactions within MAO and HTR1A binding pockets, supported by shared pharmacophoric features. These computational findings provide a preliminary, hypothesis-generating basis suggesting that oxazolidinone-induced toxicity may involve targets beyond MAO, highlighting HTR1A modulation as a candidate mechanism requiring dedicated in vitro and in vivo validation.