Design, synthesis, evaluation of biological activities and molecular docking and dynamic studies of novel acetazolamide analog compounds

• Published in: Journal of biomolecular structure & dynamics 2024-09, Vol.42 (14), p.7243-7256
• Main Authors: Osmaniye, Derya, Yuva, Onur, Sağlık, Begüm Nurpelin, Levent, Serkan, Ozkay, Yusuf, Kaplancıklı, Zafer Asım
• Format: Article
• Language: English
• Subjects: Acetazolamide - chemistry; Acetazolamide - pharmacology; Acetazolamide analogs; Binding Sites; CA enzyme; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrases - chemistry; Carbonic Anhydrases - metabolism; Catalytic Domain; Drug Design; Humans; Hydrogen Bonding; molecular docking; Molecular Docking Simulation; molecular dynamics; Molecular Dynamics Simulation; Molecular Structure; Protein Binding; Structure-Activity Relationship
• ISSN: 0739-1102; 1538-0254; 1538-0254
• DOI: 10.1080/07391102.2023.2239930

Modification of drugs used in the clinic is a frequently used method with regards to medicinal chemistry in the development of new drugs. Acetazolamide is a drug in clinical use as a CA inhibitor. Within the scope of this study, the 'N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl) acetamide' structure, which is acetazolamide residue, was kept constant; various mercaptan substitutions were made from methylene adjacent to the carbonyl group in the structure. Compounds 4c, 4d, 4e, 4 g, 4h, 4i, and 4j exhibited inhibitor activity against CA enzyme with IC 50 =0.238 ± 0.010, 0.161 ± 0.007, 0.067 ± 0.002, 0.084 ± 0.003, 0.033 ± 0.001, 0.049 ± 0.002 and 0.187 ± 0.008 µM, respectively. The intermolecular interactions of the promising compounds with aromatase enzyme were investigated through the SP docking approach, which revealed significant binding interaction energies associated with these compounds. To measure the stability of the compounds in the enzyme active site, dynamic studies were performed at 100 ns. In addition to the RMSD, RMSF parameters, the interaction ratios of compound 4h with amino acids in the enzyme active site and the interaction histograms were also investigated. The results obtained are quite promising. Continuous interactions were exhibited with Thr199, Glu106, His96, His94 and His119, which are important for the CA enzyme. Communicated by Ramaswamy H. Sarma