Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed antidepressants, but tremor is a common adverse effect. The molecular basis of SSRI-induced tremor remains unclear, particularly at the neuromuscular junction (NMJ), where motor neuron signaling is transmitted to muscle fibers via protein complexes such as the muscle-type nicotinic acetylcholine receptor (nAChR). Here, we present a computational study investigating potential interactions between SSRIs (fluoxetine, sertraline, and paroxetine) and NMJ proteins. Using molecular docking and molecular dynamics simulations, we modeled SSRI binding to the extracellular and transmembrane domains of nAChR. Preliminary simulations predict that SSRIs can transiently occupy noncanonical sites, altering receptor conformational dynamics and potentially affecting ion channel gating and neurotransmission. Our results provide a structural framework for understanding how SSRIs may modulate NMJ activity, offering a mechanistic explanation for drug-induced tremor. This study demonstrates the utility of computational biophysics to predict drug-protein interactions at the NMJ and lays the groundwork for designing antidepressants with reduced neuromotor side effects.
Esraa Aldkheil (Sun,) studied this question.