INTRODUCTION
Molecular docking is the most common method that has been widely used to study structure-based drug design [4], including structure–activity studies, lead optimization, finding potential leads by virtual screening and providing binding hypotheses to facilitate predictions [5] between receptors and ligands. Therefore, this technique has become a great ally in the development of drugs, because the computational costs of these studies are much lower when compared to the laboratory costs required to synthesize and pharmacologically test various substances [7]. With this in mind, this paper presents a virtual screening of a library of compounds derived from isatins with potential antiepileptic activity. Since, isatin (indole-2,3-dione) is a chemical structure derived from indole, found in the human body as a natural metabolite, possessing a wide range of pharmacological and biological actions, one of the most notable being its ability to act as an anticonvulsant agent in the structures that contain it [2].
AIMS
The aim of this work is to perform a virtual screening of a designed library of 87 compounds derived from isatins (indole-2,3-dione) with potential antiepileptic activity.
METHODS
Virtual screening aims to identify the compounds most likely to bind to the biological target. This technique has two approaches, virtual screening receptor-based (based on the molecular target) and ligand-based virtual screening [6]. This study used the receptor-based screening approach, that is, uses the 3D structure of the biological target, thus evaluating the potential affinities these molecules have against the target. To do this, molecular docking was performed using the programs AUTODOCK and AUTODOCK VINA, taking as a starting point the crystallographic structure of the GABAA receptor complexed with flumazenil, obtained from the Protein Data Bank (PDB code 6D6T). Next, the dockings were performed with the molecules from the library of 87 compounds, in order to identify the interaction and potential antiepileptic activity of these ligands.
RESULTS AND DISCUSSION
With the results, it was possible to compare the AUTODOCK and AUTODOCK VINA programs, indicating that the software is successful in its predictions. This is due to the redocking procedure, using the PDB complex (6D6T), in which it is possible to validate the method and state whether the results generated are similar to those obtained experimentally. This analysis is carried out by calculating the root mean square deviation (RMSD), which represents the deviations between atom positions obtained in the docking process and the position of the crystallographic ligand. According to the literature, RMSD values should not exceed 2.0 Å [1]. The redocking results showed energy values of -7.53 kcal/mol and -9.5 kcal/mol and RMSD values of 1.003 Å and 1.1372 Å, respectively. As the results obtained in this step are expected, it was possible to do the docking with the library of compounds derived from isatin. The AUTODOCK VINA program was chosen to generate the dockings and it was possible to rank the molecules by binding energy. The three best results were -11.4 kcal/mol, -11.0 kcal/mol and 10.4 kcal/mol, higher than the reference ligand. Therefore, with these results, it is possible to suggest that the receptor in question (GABAA) is a possible mechanism of action for these compounds, which will have to be confirmed in future binding assays.
CONCLUSION
The docking study of the library of molecules derived from isatin suggested that binding to GABAA receptor is a possible mechanism of action for these compounds. The molecules with the highest affinity for the receptor were identified for future experimental testing by our collaborators. Finally, the results obtained indicate the need for further studies, with the prospect of redocking and docking using other programs to compare the results with those obtained in this study, and the use of other molecular targets to identify the preferred active site of isatin.
ACKNOWLEDGMENT
This work was support by CAPES, LQQC and LASOM-PB.
REFERENCES
[1] BATISTA, Victor S. et al. Construção, otimização e ancoragem molecular de substâncias bioativas em biomacromoléculas: um tutorial prático. Química Nova, v. 45, p. 223-234, 2022.
[2] EMAMI, Saeed et al. Synthesis, in silico, in vitro and in vivo evaluations of isatin aroylhydrazones as highly potent anticonvulsant agents. Bioorganic Chemistry, v. 112, p. 104943, 2021.
[3] FAN, Jiyu; FU, Ailing; ZHANG, Le. Progress in molecular docking. Quantitative Biology, v. 7, p. 83-89, 2019.
[4] MENG, Xuan-Yu et al. Molecular docking: a powerful approach for structure-based drug discovery. Current Computer-Aided Drug Design, v. 7, n.2, p. 146–157, 2011.
[5] MORRIS, Garrett M.; LIM-WILBY, Marguerita. Molecular docking. Molecular modeling of proteins, p. 365-382, 2008
[6] RODRIGUES, Ricardo P. et al. Estratégias de triagem virtual no planejamento de fármacos. Revista Virtual de Química, v. 4, n. 6, p. 739-776, 2012.
[7] SOUZA, Raphael Lopes. Aplicação da técnica de ancoragem molecular na otimização do fármaco hipoglicemiante metformina. Centro Universitário Luterano de Palmas. Palmas, 2015.
Comissão Organizadora
Francisco Mendonça Junior
Pascal Marchand
Teresinha Gonçalves da Silva
Isabelle Orliac-Garnier
Gerd Bruno da Rocha
Comissão Científica
Ricardo Olimpio de Moura
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