Design, Molecular Docking, Molecular Dynamics, and Evaluation of Novel Ligands Targeting Beta-2 Adrenergic Receptor for Asthma Therapeutics

This study investigates the design and molecular docking of novel ligands targeting the beta-2 adrenergic receptor (β2AR), a critical protein involved in bronchoconstriction and asthma regulation. Utilizing molecular docking simulations, evaluated the binding affinities of proposed compounds, including the eight compounds, and the reference drug salbutamol, against β2AR. The docking studies were conducted using Glide software (Maestro 13.5) within the Schrodinger suite (Schrodinger, 2023), and binding interactions were analyzed to identify key residues responsible for ligand binding and receptor activation The MM-GBSA results indicate that all tested compounds exhibit favorable binding affinities with 7DHI, suggesting strong potential as ligands. Among them, two compounds demonstrated particularly strong binding to the β2-adrenergic receptor (β2AR), with MM-GBSA calculated binding free energies of -57.71 and -58.95 kcal/mol, closely comparable to that of salbutamol (-59.74 kcal/mol). These compounds exhibited the best stability and interaction with β2AR, underscoring their suitability for further development. The binding affinity is primarily driven by Van der Waals interactions and non-polar solvation, highlighting their strong receptor interaction and potential for optimization. Key residues such as SER 207, PHE 289, LYS 305, and ASP 192 played significant roles in stabilizing the receptor-ligand interactions. The inclusion of functional groups like NO₂ and NC was based on their demonstrated favorable interactions with the binding site, which enhanced affinity. While these groups contributed positively to binding, these findings indicate that further structural modifications—beyond these specific functionalities—may optimize β2AR binding even further. These insights into the molecular mechanisms underlying β2AR-ligand interactions highlight the potential of compounds as promising candidates for further development into β2 agonists for asthma treatment. Salbutamol, as a well-established β2 agonist, served as a benchmark for evaluating the efficacy of the novel ligands, confirming the feasibility of designing β2AR-targeting therapeutics with improved potency and selectivity.