Discovery of GABA Aminotransferase Inhibitors via Molecular Docking, Molecular Dynamic Simulation, and Biological Evaluation

Abstract

γ-Aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that degrades γ-aminobutyric (GABA) in the brain. GABA is an important inhibitory neurotransmitter that plays important neurological roles in the brain. Therefore, GABA-AT is an important drug target that regulates GABA levels. Novel and potent drug development to inhibit GABA-AT is still a very challenging task. In this study, we aimed to devise novel and potent inhibitors against GABA-AT using computer-aided drug design (CADD) tools. Since the crystal structure of human GABA-AT was not yet available, we utilized a homologous structure derived from our previously published paper. To identify highly potent compounds relative to vigabatrin, an FDA-approved drug against human GABA-AT, we developed a pharmacophore analysis protocol for 530,000 Korea Chemical Bank (KCB) compounds and selected the top 50 compounds for further screening. Preliminary biological analysis was carried out for these 50 compounds and 16 compounds were further assessed. Subsequently, molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations were carried out. In the results, four predicted compounds, A07, B07, D08, and H08, were found to be highly potent and were further evaluated by a biological activity assay to confirm the results of the GABA-AT activity inhibition assay.

Discovery of Novel Aldose Reductase Inhibitors via the Integration of Ligand-Based and Structure-Based Virtual Screening with Experimental Validation

“…This includes contributions from various intermolecular forces, for instance, hydrogen bonding, van der Waals forces, and electrostatic interactions, collectively influencing the binding affinity. CDocker interaction energy offers detailed insights into the intensity and nature of specific interactions between the ligand and the receptor . Therefore, FDA-approved and Enamine compound libraries, as well as known aldose inhibitors from MCE such as Epalrestat and Ponalrestat, were docked against aldose reductase individually scored based on the minimum docking energy and interaction energy values (Table ).…”

“…CDocker interaction energy offers detailed insights into the intensity and nature of specific interactions between the ligand and the receptor. 39 Therefore, FDA-approved and Enamine compound libraries, as well as known aldose inhibitors from MCE such as Epalrestat and Ponalrestat, were docked against aldose reductase individually scored based on the minimum docking energy and interaction energy values ( Table 2 ). Aldose reductase-IN-2 (compound 5f), which is an investigational potent aldose reductase inhibitor, demonstrated the most stable interaction with the enzyme.…”

Drug Repositioning via Graph Neural Networks: Identifying Novel JAK2 Inhibitors from FDA-Approved Drugs through Molecular Docking and Biological Validation

“…Molecular docking is the most commonly used method for the evaluation of the interactions and conformations of ligands against the target proteins [ 49 ]. It anticipates the association strength or binding compatibility between ligand and protein based on preferred orientation by using scoring algorithms [ 40 , 50 ]. The waters and the ligand molecule were removed from the receptor and the hydrogens were added by Discovery Studio’s protein preparation module, prior to docking.…”