In search of a photoswitchable drug for serotonin receptors: a molecular dynamics simulation study

G-protein-coupled receptors are membrane-bound proteins that control physiological and psychological activities such as hormonal regulation, sensory signaling and neurotransmission in the human body. The photoisomerization capability of azobenzenes has enabled the development of a new generation of photoswitchable drugs that offer greater efficacy while reducing the side effects typical of conventional treatments. Serotonin binding to the serotonin receptor can be controlled by conjugating it with <i>cis</i> and <i>trans</i> photoswitchable isomers of azobenzene at the hydroxyl position. We have used a combination of molecular dynamics (MD) simulation and free-energy methods for receptor binding to <i>trans</i>-azobenzene-fused-serotonin (TAS) and <i>cis</i>-azobenzene-fused serotonin (CAS) ligand systems. The CAS ligand experienced greater conformational fluctuations in comparison to the TAS ligand. Binding free-energy values showed significant differences between the CAS-receptor and TAS-receptor complexes, indicating that the TAS ligand binds actively to the serotonin receptor as compared to the CAS ligand. It also revealed that the presence of a lipid membrane has a strong influence on the stability and dynamics of the receptor-ligand complex and, thus, on the differential binding free-energy values. The change in binding free energy between the CAS-receptor and TAS-receptor complexes is found to be entropically driven. A qualitative and quantitative analysis of the stacking interactions between aromatic residues of interest and each ligand indicates that T-type stacking interactions predominate and particularly Trp327 and Phe330 residues contribute notably to the stability of the TAS-receptor complex. The study indicates that by leveraging the photoswitchable properties of azobenzenes, a photoswitchable serotonin-based drug with tunable binding affinity can be designed, which may facilitate advanced drug discovery and therapeutic approaches for mental health treatments.