Comparative Molecular Docking and Toxicity Profiling of Buspirone and Tandospirone Targeting the HTR1A Receptor

The human serotonin 1A (5-HT1A/HTR1A) receptor is a central target in the treatment of anxiety and mood disorders. However, ligand efficacy is sensitive to receptor conformation. Both Buspirone and Tandospirone are clinically relevant 5-HT1A agonists. This comparative in silico analysis was performed to examine their binding behavior and toxicity profiles. Molecular docking was performed on the serotonin-bound HTR1A receptor (PDB ID: 7E2Y) using SwissDock, and the toxicological predictions were generated with ProTox 3.0. Both ligands exhibited the greatest binding affinity for Chain A of the receptor (-6.14 kcal/mol for Buspirone and -5.88 kcal/mol for Tandospirone), suggesting a preferred receptor conformation that may mediate therapeutic efficacy. Buspirone demonstrated greater binding stability than Tandospirone across models. Both compounds demonstrated weak or unstable interactions for chains G and R. Predicted toxicity profiles revealed high probabilities of neurotoxicity and respiratory toxicity for both ligands, with blood–brain barrier penetration probabilities of 0.99 (Buspirone) and 1.00 (Tandospirone).

Additionally, Tandospirone showed potential immunotoxic effects (probability 0.73). These findings demonstrated that the receptor conformation in ligand binding enhances efficacy in drug design while reducing CNS-related adverse effects. Overall, this comparative study provides a starting point that may inform the design of next-generation serotonergic therapeutics for mood and anxiety disorders.