ADME/Tox Study and Molecular Dynamics Simulations Applied in the Design of New Potential GABA-AT Inhibitors

Chalcones derivatives compounds possess several biological activities. 08 molecules were selected from the literature. PASS Server was used to predict biological activities of chalcones (1–4) and dihydrochalcones (5–8). Pharmacokinetic and toxicological properties (ADME/Tox) of chalcones derivatives were calculated via preADMET Server. We investigated the interaction mode of selected compounds against GABA aminotransferase (GABA-AT) -PDB code 4Y0I- target indicated by PASS, using GOLD program in our molecular docking study. Our analysis was based on the interactions with Glu270, Arg445, Lys329, and Arg192 present in the active site, and indicated compounds 2, 5, and 6 as the most promising inhibitors. Molecular dynamics (MD) simulations were carried out via Biovia Discovery Studio software, based on the CHARMm force-field engine, using as input top-ranked docking poses obtained for the selected 2, 5, and 6, regarding the same crystallographic GABA-AT enzyme structure. Our results showed these compounds could bind strongly to plasma proteins, with a variation in the range of 90.21% to 100%. Compound 5 exhibited CBrain/CBlood = 1.07505 considered active in the CNS, while compounds 2 and 6 showed low values 0.34815 and 0.28086, respectively, therefore regarded as inactive. Analyses of RMSDs obtained for such three chalcones reveal a higher stabilization for the complex GABA-AT enzyme-chalcone 6, since a lower fluctuation of RMSD values is for it observed (from 4.0 to 7.0 Ǻ), in comparison with the values obtained for GABA-AT enzyme-chalcone 2 (RMSD from 2.5 to 8.5 Ǻ, the less stable) and GABA-AT enzyme-chalcone 5 (RMSD from 2.5 to 7.0).