Coumarin benzamide scaffold as potential 5-HT_2C inhibitors: a multiparametric investigation and molecular simulation

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.

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.