Physicochemical Insights on Terahertz Wave Diminished Side Effects of Drugs from Slow Dissociation

Dopamine D2 receptors (D2Rs) are one of the most intensely investigated and well-established drug targets for neuropsychiatric disorders. Selective D2R antagonists have been developed as efficacious antipsychotic drugs. Nevertheless, the potent drugs with necessarily high affinity are prone to slow dissociation, which invokes a plethora of severe side effects such as extrapyramidal symptoms, substantial weight gain, associated diabetes, etc. This has become a major barrier in treating psychiatric patients. In this work, we propose a physical method, terahertz wave modulation, to promote the dissociation of high-affinity antipsychotics and thus diminish the side effects. We have proven that a 4.0 THz wave could reduce the affinity by 71% between the D2R and a risperidone ligand and meanwhile expand the exit via conformation modulation, which promises an accelerated dissociation of risperidone. In addition, it is estimated that the enhancement of the dissociation rate due to lowered binding by terahertz irritation could constitute up to 8 orders of magnitude, which is fairly impressive and resembles the enzyme's catalysis. Also, acceleration of the dissociation rate could be adjusted by the irritation strength. This work elaborates the terahertz wave-modulated noncovalent interactions critical in cell signaling pathways. Most importantly, it demonstrates the feasibility of terahertz technologies intervening in receptor-ligand complex regulated diseases such as neurodegenerative disorders, metabolic diseases, etc.