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Computational evidence for nitro derivatives of quinoline and quinoline N-oxide as low-cost alternative for the treatment of SARS-CoV-2 infection. Scientific Reports

Por: Letícia C. Assis; Alexandre A. de Castro; João P. A. de Jesus; Eugenie Nepovimova; Kamil Kuca; Teodorico C. Ramalho; Felipe A. La Porta

Autor contato: Teodorico C. Ramalho (teo@ufla.br)

Resumo
A new and more aggressive strain of coronavirus, known as SARS-CoV-2, which is highly contagious, has rapidly spread across the planet within a short period of time. Due to its high transmission rate and the significant time–space between infection and manifestation of symptoms, the WHO recently declared this a pandemic. Because of the exponentially growing number of new cases of both infections and deaths, development of new therapeutic options to help fight this pandemic is urgently needed. The target molecules of this study were the nitro derivatives of quinoline and quinoline N-oxide. Computational design at the DFT level, docking studies, and molecular dynamics methods as a well-reasoned strategy will aid in elucidating the fundamental physicochemical properties and molecular functions of a diversity of compounds, directly accelerating the process of discovering new drugs. In this study, we discovered isomers based on the nitro derivatives of quinoline and quinoline N-oxide, which are biologically active compounds and may be low-cost alternatives for the treatment of infections induced by SARS-CoV-2.

Publicado em: Scientific Reports (Nature) (2021)

Artigo completo: https://doi.org/10.1038/s41598-021-85280-9


Conformational fingerprints in the modeling performance of MIA-QSAR: A case for SARS-CoV protease inhibitors

Por: Joyce K. Daré; Daniela R. Silva; Teodorico de Castro Ramalho; Matheus P. Freitas

Autor contato: Joyce K. Daré

Resumo
Multivariate image analysis applied to quantitative structure–activity relationships (MIA-QSAR) has proved to be a high-performance 2D tool for drug design purposes. Nonetheless, MIA-QSAR strategy does not efficiently incorporate conformational information. Therefore, understanding the implications of including this type of data into the MIA-QSAR model, in terms of predictability and interpretability, seems a crucial task. Conformational information was included considering the optimised geometries and the docked structures of a series of disulfide compounds potentially useful as SARS-CoV protease inhibitors. The traditional analysis (based on flat-shape molecules) proved itself as the most effective technique, which means that, despite the undeniable importance of conformation for biomolecular behaviour, this type of information did not bring relevant contributions for MIA-QSAR modelling. Consequently, promising drug candidates were proposed on the basis of MIA-plot analyses, which account for PLS regression coefficients and variable importance in projection scores of the MIA-QSAR model.

Palavras-chave: SARS-CoV, QSAR, molecular docking, conformation

Publicado em: MOLECULAR SIMULATION (2020)

Artigo completo: https://doi.org/10.1080/08927022.2020.1800691


Effect of drug metabolism in the treatment of SARS-CoV-2 from an entirely computational perspective

Por: João de Jesus; Letícia Assis; Alexandre Assis ; Elaine Cunha; Eugenie Nepovimova; Kamil Kuca; Teodorico Ramalho; Felipe La Porta

Autor contato: Teodorico C. Ramalho (Parceria : prof. Elaine F.F. da Cunha (DQI)) (teo@ufla.br)

Resumo
Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.

Palavras-chave: Computational Strategies, Side Effects, Electron Ionization Mass Spectroscopy, Molecular Docking, ADMET Model

Publicado em: Research Square (2021)

Artigo completo: https://doi.org/10.21203/rs.3.rs-402547/v1


Interactions of Ozone-Functionalized Activated Charcoal with SARS-Cov-2 Proteases Using Molecular Docking and Dynamics.

Por: ARAUJO, H. D. C.; AROUCHE, T. S.; CARVALHO JUNIOR, R. N.; RAMALHO, T. C.; BORGES, R. S.; OLIVEIRA, M. S.; MARQUES, F. C.; CHAVES NETO, A. M. J.

Autor contato: Teodorico C. Ramalho (teo@ufla.br)

Resumo
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Publicado em: Journal of Nanoscience and Nanotechnology (2021)

Artigo completo: https://doi.org/10.1166/jnn.2021.19029


Molecular Docking of Azithromycin, Ritonavir, Lopinavir, Oseltamivir, Ivermectin and Heparin Interacting with Coronavirus Disease 2019 Main and Severe Acute Respiratory Syndrome Coronavirus-2 3C-Like Proteases.

Por: Tiago da Silva Arouche; Anderson Yuri Martins; Teodorico de Castro Ramalho; Raul Nunes de Carvalho Júnior; Fábio Luiz Paranhos Costa; Tarciso Silva de Andrade Filho; Antônio Maia Jesus Chaves Neto

Autor contato: Teodorico de Castro Ramalho (teo@ufla.br)

Resumo
In the current pandemic situation raised due to COVID-19, drug reuse is emerging as the first line of treatment. The viral agent that causes this highly contagious disease and the acute respiratory syndrome coronavirus (SARS-CoV) share high nucleotide similarity. Therefore, it is structurally expected that many existing viral targets are similar to the first SARS-CoV, probably being inhibited by the same compounds. Here, we selected two viral proteins based on their vital role in the viral life cycle: Structure of the main protease SARS-CoV-2 and the structural base of the SARS-CoV-2 protease 3CL, both supporting the entry of the virus into the human host. The approved drugs used were azithromycin, ritonavir, lopinavir, oseltamivir, ivermectin and heparin, which are emerging as promising agents in the fight against COVID-19. Our hypothesis behind molecular coupling studies is to determine the binding affinities of these drugs and to identify the main amino acid residues that play a fundamental role in their mechanism of action. Additional studies on a wide range of FDA-approved drugs, including a few more protein targets, molecular dynamics studies, in vitro and biological in vivo evaluation are needed to identify combination therapy targeted at various stages of the viral life cycle. In our experiment in silico, based mainly on the molecular coupling approach, we investigated six different types of pharmacologically active drugs, aiming at their potential application alone or in combination with the reuse of drugs. The ligands showed stable conformations when analyzing the affinity energy in both proteases: ivermectin forming a stable complex with the two proteases with values −8.727 kcal/mol for Main Protease and −9.784 kcal/mol for protease 3CL, Heparin with values of −7.647 kcal/mol for the Main protease and −7.737 kcal/mol for the 3CL protease. Both conform to the catalytic site of the proteases. Our studies can provide an insight into the possible interactions between ligands and receptors, through better conformation. The ligands ivermectin, heparin and ritonavir showed stable conformations. Our in-silica docking data shows that the drugs we have identified can bind to the binding compartment of both proteases, this strongly supports our hypothesis that the development of a single antiviral agent targeting Main protease, or 3CL protease, or an agent used in combination with other potential therapies, it could provide an effective line of defense against diseases associated with coronaviruses.

Palavras-chave: Affinity Energy, COVID-19, Molecular Docking, Pharmacology, Proteases

Publicado em: Journal of Nanoscience and Nanotechnology (2021)

Artigo completo: https://doi.org/10.1166/jnn.2021.19029


New in silico insights into the application of the (hydroxy)chloroquine with macrolide antibiotics co-crystals against the SARS-CoV-2 virus

Por: Alexandre A. de Castro; Letícia C. Assis; Teodorico C. Ramalho; Felipe A. La Porta

Autor contato: Teodorico C. Ramalho (teo@ufla.br)

Resumo
In this in silico study, the different pharmaceutical co-crystals based on the (hydroxy)chloroquine with the macrolide antibiotics (azithromycin, clarithromycin, or erythromycin A) was analyzed for the first time. These findings present a new molecular perspective and, therefore, suggest that the combination of (hydroxy)chloroquine/azithromycin, in the stoichiometric ratio of 1:1, as model co-crystals systems have less toxicity as well as is the most effective for inhibiting the new coronavirus SARS-CoV-2.

Palavras-chave: (hydroxy)chloroquine, macrolide antibiotics, co-crystals, SARS-CoV-2, Molecular Modelling

Publicado em: Research Square (2020)

Artigo completo: https://doi.org/10.21203/rs.3.rs-66640/v1


Theoretical Insights into the Effect of Halogenated Substituent on the Electronic Structure and Spectroscopic Properties of the Favipiravir Tautomeric Forms and Its Implications on the Treatment of COVID-19

Por: Letícia Assis; Alexandre A. de Castro; João Paulo A. de Jesus; Teodorico Ramalho; Felipe La Porta

Autor contato: Teodorico C. Ramalho (teo@ufla.br)

Resumo
In this study, we systematically investigated the electronic structure, spectroscopic (nuclear magnetic resonance, infrared, Raman, electron ionization mass spectrometry, UV-Vis, circular dichroism, and emission) properties, and tautomerism of halogenated favipiravir compounds (fluorine, chlorine, and bromine) from a computational perspective. Additionally, the effects of hydration on the proton transfer mechanism of the tautomeric forms of the halogenated favipiravir compounds are discussed. Our results suggest that spectroscopic properties allow for the elucidation of such tautomeric forms. As is well-known, the favipiravir compound has excellent antiviral properties and hence was recently tested for the treatment of new coronavirus (SARS-CoV-2). Through in silico modeling, in the current study, we evaluate the role of such tautomeric forms in order to consider the effect of drug-metabolism into the inhibition process of the main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 virus. These findings clearly indicated that all title compounds are better as RNA-inhibiting.

Palavras-chave: Favipiravir, COVID-19, In silico modeling, Tautomers, Electronic structure, spectroscopic properties

Publicado em: Theoretical and Computational Chemistry (2020)

Artigo completo: https://doi.org/10.26434/chemrxiv.12977597.v1