Introduction: Coronaviruses (CoVs) are RNA viruses, belonging to the alpha-CoV genus, with a single-stranded and positive-stranded structure that have large viral genomes, ranging in size from 26 to 32 kilobases [1–3]. Currently, there are six variables of CoVs that affect humans, these corresponding to: the alpha-CoVs, HCoV-229E and HCoV-NL63, and the beta-CoVs, HCoVOC43, HCoV-HKU1, SARS-CoV and MERS-CoV [1]. 2019-n-CoV is the seventh coronavirus known to infect humans and cause serious illness. The outbreak of coronavirus disease (Covid 19) caused a global public health crisis due to the rapid and massive contagion of the population and the limited potential for care in the health system. In this context, it is necessary to search for new therapeutic alternatives, thus selenium compounds are mentioned, given that, in recent years, the potential therapeutic effects of selenium on already known biological activities such as antitumor and antioxidant activity [4,5], has attracted attention and aroused interest in the application of compounds derived from this element in new activities, which include antimicrobial activities [6], antifungal [7] and antiviral. In addition to the constant search for new agents, the use of new methodologies for study and development has been mentioned, such as virtual screening techniques through the use of in silico studies, which carry out the selection of compounds with potential activity to from existing databases, which contributes to optimizing study duration and reducing costs [8].
Objective: The present work aims to carry out a virtual screening of selenium compounds derived from ethylenelactic acid, which are called selenoethylenelacticamides against SARS-CoV-2 proteases.
Methodology: The molecules under study are 08 compounds derived from ethylenelactic acid of synthetic origin which were called selenoethylenelacticamides, which were drawn in the software Marvin Sketch 19.18 (https://chemaxon.com/), then the minimization of the chemical structures of compounds in the Spartan 14 program (https://www.wavefun.com/), and conversion to the 3D structure using the Molecular Mechanics method. To carry out the Molecular Docking simulations, the target proteins and their respective ligands were searched in the Protein Data Bank (PDB) library (https://www.rcsb.org/), corresponding respectively to: Main-Protease in complex with ligand NCL-00024905 (PDB: 5RG1) [9], resolution: 1.65 Å; Papain like protease (PDB: 7JRN) [10], resolution: 2.48 Å and SPIKE protein (PDB: 7JN5) [11], resolution: 2.71 Å. Before carrying out the Molecular Docking simulation, the Redocking stage was carried out, in order to validate the Docking carried out later. Both procedures were performed using the Molegro Virtual Docker (MVD) v.6.0.1 software. Enzymes and compounds were prepared according to the predefined parameters in the software. In the coupling procedure (ligand-enzyme), a Grid of 15 Å radius and 0.30 resolution was used, which involved the location of the binding site, defined through a known ligand for each enzyme. A model was generated in order to perform and evaluate the fit with expected characteristics between the ligand and the enzyme, using the MOLDOCK Score algorithm (GRID) with the scoring function and search algorithm, corresponding to Moldock. The visualization of established interactions was carried out using the Discovery Studio Visualizer program, Biovia, 2020 (https://www.3dsbiovia.com/).
Results: Molecular docking was carried out in order to evaluate the structural groups of the compounds under study that contribute to the antiviral effect. Before carrying out Docking, redocking was simulated, which was calculated only for the target Main-protease (PDB: 5RG1) and Papain like protease (PDB: 7JRN), which are the only 3D structures that present a co-crystallized ligand. The value obtained corresponded to respectively: 0.3525 and 0.2364, indicating that it is within the values considered acceptable for the quadratic deviation of the structure. The selenoethylenelacticamide derivatives presented negative binding energy values to molecular targets, indicating a prediction of affinity with all targets evaluated, mainly with the Main-protease target (PDB: 5RG1), in which compound 8 presented the lowest binding energy value. bond (-115,173 KJ.mol -1 ), followed by compound 04 (-108,723 KJ.mol -1) and when compared to the PDB ligand (-104,366 KJ.mol -1). Regarding the interaction maps of compound 08 with the Main protease enzyme (PDB: 5RG1) it can be seen that the highest number of interactions were observed in the benzocaine group, these corresponding to four hydrophobic interactions of the alkyl, pi-alkyl, pi-pi T-shaped through residues: Met 165 (1 interaction), His 41 (2 interactions), Met 49 (1 interaction); one unfavorable interaction through Met residue 49 and two hydrogen bond-type interactions through His residue 41 (1 interaction) and Asp 187 (1 interaction). Two hydrogen bond-type interactions were also observed in the amide group through residues Asn 142 (1 interaction) and Leu 141 (1 interaction) and an Amide-Pi Stacked type interaction through residue Leu 141. It is worth noting that they were Important residues were observed, such as Met residue 49, which is an important residue for the plasticity of the enzyme, and His residue 41, which is an important catalytic residue for maintaining activity. The PDB ligand presented hydrogen bond-type interactions through residues His 41 (1 interaction), His 164 (1 interaction), Asn 142 (1 interaction), Phe 140 (1 interaction). In addition to an Amide Pi-stacked type interaction through residue Leu 141 and a pi-sulfur type interaction through Cys residue 145. It is worth noting that similar interactions were observed between the PDB ligand and compound 08 that corresponded to the residue His 41 and Cys residue 145.
Conclusion: The computational study carried out made it possible to evaluate the affinity of interaction of compounds derived from selenoethylene lactamides with SARS-CoV-2 proteases and identification of a possible mechanism, with M-protease being the target in which the lowest energies were observed.
References:
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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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