DFT and Molecular Dynamics Guided Pharmacokinetic Evaluation of Phenyl Styryl Ketone Derivatives as Potential MAO‐B Inhibitors

ABSTRACT This research explores the capacity of phenyl styryl ketone derivatives to inhibit monoamine oxidase B (MAO‐B), a key enzyme associated with neurodegenerative disorders. From frontier molecular orbital (FMO) studies, reactivity parameters of the drug candidates were found out. Ligands were submitted to absorption, digestion, metabolism, excretion, and toxicity (ADMET) analysis to ensure their potential drugability and safety. To understand the electronic description of ligand interaction, natural bond orbital (NBO) analysis was conducted, and the presence of heteroatoms was proven crucial. The reduced density gradient (RDG) studies, together with molecular electrostatic surface potential (MESP) analysis, were able to provide the ligand's active sites and nature of interaction. Docking studies were conducted to study the interaction between the protein (P) and ligand (L) at the MAO‐B catalytic region, alongside a comparison with safinamide, a recognized MAO‐B inhibitor. Molecular dynamics (MD) simulations were utilized to examine the protein–ligand complex (PLC). The molecular mechanics Poisson–Boltzmann surface area (MM‐PBSA) method was applied to predict the binding affinity and interaction. We also analyzed structural stability, solvation, and decomposition. Of the four ligands examined, CHA_1.4 is found to be the most efficient. The contact map method was useful in identifying the key amino acids; in all the complexations we have considered, TYR398 has interacted most with the drug candidates. The finding was in agreement with the decomposition profile of the PLC. For the principal component analysis (PCA), topology formats and 100 ns MD trajectories are used to learn more about how proteins fold. Replicates were also done to validate the reported study and are represented as box‐whisker plots. The study's findings provide valuable insights for the development of new MAO‐B inhibitors.