Deciphering the 4′,7‐Dihydroxy‐3′‐Methylflavone from Boerhavia, Agonist/Antagonist Interactions Against 5‐HT₂ Receptors using Homology Modeling, Molecular Docking, and Dynamic Simulation Studies

Abstract

Seizures, depression, and anxiety are neurological disorders that affected innumerable people worldwide. Recent research has revealed that targeting 5‐hydroxytryptamine 2 (5‐HT2) receptors can help suppress these conditions. An in‐depth literature study has identified that phytocompounds from the Boerhavia genus could reduce seizures. Therefore, homology models of 5‐HT2 receptors were generated and validated using techniques such as the alignment of amino acid sequences and the Ramachandran plot. Later, a comparison of modeled structures was made with a non‐redundant set of PDB structures. The pharmacokinetics, drug‐likeness, blood‐brain barrier (BBB) permeability, and Lipinski’s rule of five shed light on 22 phytocompounds, which are the potential candidates for molecular docking among 127 Boerhavia’s bioactive. Notably, molecular docking analysis revealed 4ʹ,7‐dihydroxy‐3ʹ‐methylflavone as the most potent lead compound, which has a strong binding affinity to all modeled receptors. Additionally, with a remarkably high docking score of ‐9.1 kcal/mol, 4ʹ,7‐dihydroxy‐3ʹ‐methylflavone showed promising interactions, particularly with 5‐HT2A receptor, as seen from the RMSD, SASA, Rg, and number of hydrogen bonds during 100 ns molecular dynamic (MD) simulation. Principal component analysis (PCA) and Molecular Mechanics‐Poisson‐Boltzmann Surface Area (MM‐PBSA) further confirmed that 4ʹ,7‐dihydroxy‐3ʹ‐methylflavone is the best novel phytocompound in Boerhavia genus for 5‐HT2 receptor as agonist/antagonist activity against seizures.