QSAR analysis of Multimodal Antidepressants Vortioxetine Analogs using Physicochemical Descriptors and MLR Modeling.

BACKGROUND: Vortioxetine is a multimodal antidepressant drug with combined effects on SERT as inhibitor, 5-HT1A as agonist and 5-HT3A as antagonist. Series of vortioxetine analogs have been reported as multi antidepressant compounds and they block serotonin transport into the neuronal cells, activate the postsynaptic 5-HT1A receptors and eliminate the low activity of 5-HT3A receptors.

OBJECTIVE: To explore the important properties of vortioxetine analogs involved in antidepressant activity by developing 2D QSAR models.

METHODS: Selections of significant descriptors were performed by least absolute shrinkage and selection operator (LASSO) method and, the multiple linear regression (MLR) method and All Subsets and GA algorithm included in QSARINS software were used for generating QSAR models. Further, the virtual screening was performed based on bioactivity and structure similarity using the PubChem database.

RESULTS: The four descriptor model of complementary information content (CIC2), solubility (bcutp3), mass (bcutm8) and partial charge in van der Waals surface area (PEOEVSA7) of the molecules is obtained for SERT inhibition with the significant statistics of R2= 0.69, RMSEtr= 0.44, R2ext= 0.62 and CCCext= 0.78. For 5-HT1A agonist, the two descriptor model of molecular shape (Kappm3) and van der Waals volume of the atoms (bcutv11) with R2= 0.78, RMSEtr= 0.33, R2ext = 0.83, and CCCext= 0.87 is established. The three descriptor model of information content (IC3), solubility (bcutp9) and electronegativity (GATSe5) of the molecules with R2= 0.61, RMSEtr= 0.34, R2ext= 0.69 and CCCext= 0.72 is obtained for 5-HT3A antagonist. The antidepressant activities of 16 virtual screened compounds were predicted using the developed models.

CONCLUSIONS: The developed QSAR models may be useful to predict antidepressant activity for the newly synthesized vortioxetine analogs.