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Context <p> This study investigates the interaction of synthetic coumarin benzamides (<b>CmB1</b>-<b>10</b>) obtained from the literature with the 5-HT2CR serotonergic receptor and the carbonic anhydrase II (CA-II) enzyme, with potential pharmacological applications in anxiety disorders. CmB is a type of drug that has been shown to affect the 5-HT2CR receptor. This receptor is involved in mood, thinking, and muscle control. CmB has similar effects to other known antagonists. In addition, the dimethylated derivatives (3,4-CH3 and 3,5-CH3)—<b>CmB2</b> and <b>CmB4</b>—were more effective as enzyme inhibitors, according to the literature. Structural analyses revealed that the <b>CmB2</b> and <b>CmB4</b> derivatives exhibit a higher nucleophilic character due to the electron-donating properties of the dimethyl substituents. The dimethylated derivatives exhibited ideal pharmacokinetic properties, including an apparent permeability (Papp, A→B 1.1&#xa0;×&#xa0;10⁻<sup>5</sup>&#xa0;cm/s) and metabolic stability. The virtual screening revealed the structural specificity of the compounds for CA-II and 5-HT2CR, with affinity energy for 5-HT2CR –&#xa0;10&#xa0;kcal/mol. Molecular dynamics simulations estimated a low binding free energy (ΔG) of the lead compounds to about 5-HT2CR, indicating that they were energetically more stable complexes. This research provides a basis for future experimental studies that corroborate the neuromodulatory action of CmB derivatives.</p> Methods <p> This study utilized the integration of molecular modeling techniques at quantum levels (DFT/B3LYP/6-311++G(d,p)) using the Gaussian 09 program to investigate structural/electronic properties and classical levels such as molecular docking and molecular dynamics, using the AutoDockVina™ and GROMACS® programs respectively, to investigate the interaction between meanings and biological targets (5-HT2CR and CA-II). DMPK was used to investigate the bioavailability and metabolism of the drugs from the results.</p>

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Coumarin benzamide scaffold as potential 5-HT2C inhibitors: a multiparametric investigation and molecular simulation

  • 期刊论文

  • 发表日期：

    2025年12月13日

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  • Akenaton Onassis Cardoso Viana Gomes,
  • Francisco Nithael Melo Lúcio,
  • Matheus Nunes da Rocha,
  • Victor Moreira de Oliveira,
  • Caio Henrique Alexandre Roberto,
  • Márcia Machado Marinho,
  • Hélcio Silva dos Santos,
  • Pedro de Lima-Neto,
  • Emmanuel Silva Marinho

摘要

Context

This study investigates the interaction of synthetic coumarin benzamides (CmB1-10) obtained from the literature with the 5-HT2CR serotonergic receptor and the carbonic anhydrase II (CA-II) enzyme, with potential pharmacological applications in anxiety disorders. CmB is a type of drug that has been shown to affect the 5-HT2CR receptor. This receptor is involved in mood, thinking, and muscle control. CmB has similar effects to other known antagonists. In addition, the dimethylated derivatives (3,4-CH3 and 3,5-CH3)—CmB2 and CmB4—were more effective as enzyme inhibitors, according to the literature. Structural analyses revealed that the CmB2 and CmB4 derivatives exhibit a higher nucleophilic character due to the electron-donating properties of the dimethyl substituents. The dimethylated derivatives exhibited ideal pharmacokinetic properties, including an apparent permeability (Papp, A→B 1.1 × 10⁻5 cm/s) and metabolic stability. The virtual screening revealed the structural specificity of the compounds for CA-II and 5-HT2CR, with affinity energy for 5-HT2CR – 10 kcal/mol. Molecular dynamics simulations estimated a low binding free energy (ΔG) of the lead compounds to about 5-HT2CR, indicating that they were energetically more stable complexes. This research provides a basis for future experimental studies that corroborate the neuromodulatory action of CmB derivatives.

Methods

This study utilized the integration of molecular modeling techniques at quantum levels (DFT/B3LYP/6-311++G(d,p)) using the Gaussian 09 program to investigate structural/electronic properties and classical levels such as molecular docking and molecular dynamics, using the AutoDockVina™ and GROMACS® programs respectively, to investigate the interaction between meanings and biological targets (5-HT2CR and CA-II). DMPK was used to investigate the bioavailability and metabolism of the drugs from the results.