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Revealing Vilazodone’s Binding Mechanism Underlying Its Partial Agonism to 5-HT1A Receptor in the Treatment of Major Depressive Disorder

Abstract

The major depressive disorder (MDD) has been estimated as the second largest global burden among all diseases by 2030. Various types of drugs were approved and became the primary or first-line medications prescribed for MDD, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin partial agonist/reuptake inhibitors (SPARIs), and so on. SPARI was expected to demonstrate more enhanced drug efficacy and rapid onset of action compared with SSRI and SNRI. As one of the most famous SPARIs, vilazodone was approved by FDA for treating MDD. Because of its great clinical importance, vilazodone’s binding mechanism underlying its partial agonism to 5-HT1A receptor (5-HT1AR) could provide valuable information to SPARIs’ drug-like property. However, no such mechanism had yet been reported, which severely hampered the rational design of new efficacious SPARI based MDD drugs. To explore vilazodone’s molecular mechanism, an integrated computational strategy was adopted in this study to reveal its binding mechanism and prospective structural feature in the agonist binding site of 5-HT1AR. As a result, 22 residues of this receptor were identified as “hotspot” consistently favoring the binding of vilazodone and its analogues, and a common binding mechanism underlying their partial agonism to 5-HT1AR was therefore discovered. Moreover, three main interaction features between vilazodone and 5-HT1AR were revealed and schematically summarized. In summary, this newly identified binding mechanism provided valuable information to the medicinal chemists conducting rational design of novel SPARIs for MDD treatment.

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Publication details

The article was received on 20 Aug 2017, accepted on 06 Oct 2017 and first published on 09 Oct 2017


Article type: Paper
DOI: 10.1039/C7CP05688E
Citation: Phys. Chem. Chem. Phys., 2017, Accepted Manuscript
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    Revealing Vilazodone’s Binding Mechanism Underlying Its Partial Agonism to 5-HT1A Receptor in the Treatment of Major Depressive Disorder

    G. Zheng, W. Xue, F. Yang, Y. Zhang, Y. Chen, X. Yao and F. Zhu, Phys. Chem. Chem. Phys., 2017, Accepted Manuscript , DOI: 10.1039/C7CP05688E

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