Comparison of Performance of Docking, LIE, Metadynamics and QSAR in Predicting Binding Affinity of Benzenesulfonamides

• Published in: Current computer-aided drug design Vol. 11; no. 3; p. 237
• Main Authors: Raškevičius, Vytautas, Kairys, Visvaldas
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01-01-2015
• Subjects: Benzenesulfonamides; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Drug Discovery; Isoenzymes - metabolism; Molecular Docking Simulation; Quantitative Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonamides - pharmacology
• ISSN: 1875-6697
• DOI: 10.2174/1573409911666150916092624

The design of inhibitors specific for one relevant carbonic anhydrase isozyme is the major challenge in the new therapeutic agents development. Comparative computational chemical structure and biological activity relationship studies on a series of carbonic anhydrase II inhibitors, benzenesulfonamide derivatives, bearing pyrimidine moieties are reported in this paper using docking, Linear Interaction Energy (LIE), Metadynamics and Quantitative Structure Activity Relationship (QSAR) methods. The computed binding affinities were compared with the experimental data with the goal to explore strengths and weaknesses of various approaches applied to the investigated carbonic anhydrase/inhibitor system. From the tested methods initially only QSAR showed promising results (R2=0.83-0.89 between experimentally determined versus predicted pKd values.). Possible reasons for this performance were discussed. A modification of the LIE method was suggested which used an alternative LIE-like equation yielding significantly improved results (R2 between the experimentally determined versus the predicted ΔG(bind) improved from 0.24 to 0.50).