Triagem virtual de derivados de isatina com potencial atividade antiepiléptica baseada na estrutura do receptor

Abstract

Epilepsy is one of the most common brain disorders, affecting approximately 50 million people worldwide. It is characterized by spontaneous seizures, which can be either partial or generalized. The primary treatment consists of anticonvulsant medications, but many patients do not respond significantly and suffer from side effects, making the study and investigation of new drugs essential to reduce adverse effects. Computational studies have proven to be a promising tool in drug development, as the discovery and development process is time-consuming and resource-intensive due to the large number of molecular structures that must be evaluated. Thus, this study aims to conduct a structure-based virtual screening using molecular docking on a library of isatin-derived compounds, employing the Autodock Vina and GOLD programs. The screening results revealed that three molecules exhibited binding affinity (with energy values of -11.7, -11.2, and -11.1 kcal/mol) and potential interaction modes with the GABAA receptor. The ADMET properties of these compounds were assessed using the SwissADME and Deep-PK tools, considering Lipinski's Rule of Five and important parameters such as the number of rotatable bonds, topological polar surface area, gastrointestinal absorption, blood-brain barrier penetration, P-glycoprotein interaction, cytochrome P450 interactions, AMES test, hepatotoxicity, and hERG channel inhibition. Subsequently, Molecular Dynamics (MD) simulations were performed using the AMBER force field in Gromacs version 2021.2, revealing the formation of stable ligand-receptor complexes based on RMSD and RMSF values. From the trajectories generated in the MD simulation, binding free energies were estimated using the MM/PBSA (Molecular Mechanics/Poisson-Boltzmann Surface Area) approach. This method calculates binding free energy by considering three separate components: the complex (protein-ligand), the receptor (protein), and the ligand (small molecule). The results indicated that two molecules exhibited significant energy values (-30.59 and -26.18 kcal/mol) compared to diazepam (-21.45 kcal/mol).