Glycine receptors (GlyRs) are essential for inhibitory neurotransmission in the central nervous system (CNS) and represent promising targets against neurological disorders. Several indole alkaloids from Gelsemium species have been shown to modulate GlyRs. Notably, the anxiolytic and analgesic properties of certain Gelsemium alkaloids appear to depend on GlyR modulation. However, prior studies have focused on only a few indole alkaloids, leaving the activity of other Gelsemium compound classes unexplored. This study employed an integrative in silico approach to investigate the interactions between GlyR α1 and α3 subtypes and 162 structurally diverse Gelsemium compounds. Physicochemical, pharmacokinetic, and toxicological analyses identified compounds with favorable bioavailability in the CNS. Molecular docking revealed that indolic alkaloids bind the GlyR orthosteric site with profiles comparable to the reference Gelsemium compound, gelsemine. Molecular dynamics simulations confirmed the stability and conformational integrity of selected ligand-receptor complexes. Overall, novel potential GlyR modulators were identified, with several compounds showing a promising selectivity profile towards GlyR α1 and α3 subtypes. These findings further support the therapeutic potential of Gelsemium alkaloids and provide a foundation for further pharmacological and toxicological validation.