Investigating Baxdrostat and Its Derivatives as Aldosterone Synthase Inhibitors for Resistant Hypertension: An In Silico Approach

Abstract Resistant hypertension, a severe condition affecting about 10 % of people with high blood pressure, significantly increases the risk of heart, brain, and kidney issues. This study investigates the potential of baxdrostat and its derivatives ( 1 – 22 ) as aldosterone synthase inhibitors for resistant hypertension using in silico methods. The study employed various computational methods, including molecular dynamics simulation (MD), molecular docking, frontier molecular orbital (FMO) analysis, and global chemical descriptors, to evaluate the interactions between the compounds and the target proteins. The docking results showed that compounds 2 , 5 , 7 , and baxdrostat had binding affinities of −7.8 kcal/mol, −10.9 kcal/mol, −10.6 kcal/mol, and −9.3 kcal/mol, respectively. Additionally, molecular dynamics simulations revealed that ligands 2 , 5 , and baxdrostat formed the most stable protein‐ligand complexes with aldosterone synthase. The complex of the 4FDH‐baxdrostat remained highly stable across all tested temperatures (300 K, 305 K, 310 K, and 320 K), consistently displaying low RMSD values, with the minimum observed at 305 K. Baxdrostat emerges as the most promising candidate among the compounds examined, showcasing notable potential when considering a combination of in vitro, in vivo , and now in silico data. While baxdrostat remains the primary candidate based on comprehensive in vitro, in vivo , and in silico studies, further analysis using FMO theory suggests that ligands 2 and 5 have promising potential due to their smaller Egap. To validate these findings, further clinical investigations are warranted.