In silico identification of novel allosteric inhibitors of Dengue virus NS2B/NS3 serine protease

da, Costa; Rocha, João Augusto Pereira da; Pinheiro, Alan Sena; Josino, Luiz; Gonçalves, Arlan da Silva; Lima, Anderson; Brasil, Davi do Socorro Barros

doi:10.2298/jsc210929011d

Cited by 6 publications

(2 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To describe the binding affinity of the natural products and the crystallographic inhibitor with the Mpro protein, we performed binding free energy calculations using the MM/PBSA method ( Genheden and Ryde, 2015 ) available in the AmberTools23 package ( Case et al, 2023 ), while the mathematical description was published in previous studies ( Costa et al, 2022 ). The last 10 ns of the MD simulation trajectories were used to calculate the binding free energy and the decomposition of the binding free energy.…”

Section: Methodsmentioning

confidence: 99%

Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation

da Rocha,

da Costa,

da Costa

et al. 2024

Front. Chem.

View full text Add to dashboard Cite

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is the etiological agent responsible for the global outbreak of COVID-19 (Coronavirus Disease 2019). The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a vital role in mediating viral replication and transcription. In this study, a comprehensive computational approach was employed to investigate the binding affinity, selectivity, and stability of natural product candidates as potential new antivirals acting on the viral polyprotein processing mediated by SARS-CoV-2 Mpro. A library of 288 flavonoids extracted from Brazilian biodiversity was screened to select potential Mpro inhibitors. An initial filter based on Lipinski’s rule of five was applied, and 204 compounds that did not violate any of the Lipinski rules were selected. The compounds were then docked into the active site of Mpro using the GOLD program, and the poses were subsequently re-scored using MM-GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy calculations performed by AmberTools23. The top five flavonoids with the best MM-GBSA binding free energy values were selected for analysis of their interactions with the active site residues of the protein. Next, we conducted a toxicity and drug-likeness analysis, and non-toxic compounds were subjected to molecular dynamics simulation and free energy calculation using the MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method. It was observed that the five selected flavonoids had lower MM-GBSA binding free energy with Mpro than the co-crystal ligand. Furthermore, these compounds also formed hydrogen bonds with two important residues, Cys145 and Glu166, in the active site of Mpro. Two compounds that passed the drug-likeness filter showed stable conformations during the molecular dynamics simulations. Among these, NuBBE_867 exhibited the best MM-PBSA binding free energy value compared to the crystallographic inhibitor. Therefore, this study suggests that NuBBE_867 could be a potential inhibitor against the main protease of SARS-CoV-2 and may be further examined to confirm our results.

show abstract

Section: Methodsmentioning

confidence: 99%

Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation

da Rocha,

da Costa,

da Costa

et al. 2024

Front. Chem.

View full text Add to dashboard Cite

show abstract

“…All protein-ligand complexes were equilibrated with 500 ps of MD without positional restrictions at a steady pressure prior to the production process. By using a collision frequency of 2 cm −1 and linking to a Langevin thermostat, the temperature was kept at 300 K. The SHAKE [72] algorithm and the particle mesh Ewald (PME) [73,74] approach were used to limit the bond lengths involving the hydrogen atoms, and a cutoff of 8 was applied for non-bonded interactions. Finally, without applying positional restrictions, 100 ns of time at a 300 K temperature was used for the MD simulations (production).…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Exploring Natural Alkaloids from Brazilian Biodiversity as Potential Inhibitors of the Aedes aegypti Juvenile Hormone Enzyme: A Computational Approach for Vector Mosquito Control

Costa,

Rocha

et al. 2023

Molecules

Self Cite

View full text Add to dashboard Cite

This study explores the potential inhibitory activity of alkaloids, a class of natural compounds isolated from Brazilian biodiversity, against the mJHBP enzyme of the Aedes aegypti mosquito. This mosquito is a significant vector of diseases such as dengue, zika, and chikungunya. The interactions between the ligands and the enzyme at the molecular level were evaluated using computational techniques such as molecular docking, molecular dynamics (MD), and molecular mechanics with generalized Born surface area (MMGBSA) free energy calculation. The findings suggest that these compounds exhibit a high binding affinity with the enzyme, as confirmed by the binding free energies obtained in the simulation. Furthermore, the specific enzyme residues that contribute the most to the stability of the complex with the compounds were identified: specifically, Tyr33, Trp53, Tyr64, and Tyr129. Notably, Tyr129 residues were previously identified as crucial in the enzyme inhibition process. This observation underscores the significance of the research findings and the potential of the evaluated compounds as natural insecticides against Aedes aegypti mosquitoes. These results could stimulate the development of new vector control agents that are more efficient and environmentally friendly.

show abstract

In silico studies on leishmanicide activity of limonoids and fatty acids from Carapa guianensis Aubl

de Barros,

Araujo da Costa,

Farias

et al. 2024

Front. Chem.

View full text Add to dashboard Cite

The oil of Carapa guianensis showed leishmanicidal activity, with its activity being related to limonoids, but fatty acids are the major constituents of this oil. The present study evaluated the physicochemical, pharmacokinetic, and toxicity profiles of limonoids and fatty acids already identified in the species. Based on these results, 2 limonoids (methyl angosinlate, 6-OH-methyl angosinlate) and 2 fatty acids (arachidic acid; myristic acid) were selected for the prediction of possible targets and molecular docking. Included in this study were: Gedunin, 6α-acetoxygedunin, Methyl angosenlato, 7-deacetoxy-7-oxogedunin, Andirobin, 6-hydroxy-angolensate methyl, 17β-hydroxyazadiradione, 1,2-dihydro-3β-hydroxy-7-deacetoxy-7-oxogedunin, xyllocensin k, 11beta-Hydroxygedunin, 6α,11-11β-diacetoxygedunin, Oleic Acid, Palmitic Acid, Stearic Acid, Arachidic Acid, Myristic Acid, Palmitoleic Acid, Linoleic Acid, Linolenic Acid, and Beenic Acid. Regarding physicochemical aspects, fatty acids violated LogP, and only limonoid 11 violated Lipinski’s rule. A common pharmacokinetic aspect was that all molecules were well absorbed in the intestine and inhibited CYP. All compounds showed toxicity in some model, with fatty acids being mutagenic and carcinogenic, and limonoids not being mutagenic and carcinogenic at least for rats. In in vivo models, fatty acids were less toxic. Molecular dockings were performed on COX-2 steroids (15 and 16) and hypoxia-inducible factor 1 alpha for limonoids (3,6), with this target being essential for the intracellular development of leishmania. Limonoids 3 and 6 appear to be promising as leishmanicidal agents, and fatty acids are promising as wound healers.

show abstract

In silico identification of novel allosteric inhibitors of Dengue virus NS2B/NS3 serine protease

Cited by 6 publications

References 44 publications

Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation

Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation

Exploring Natural Alkaloids from Brazilian Biodiversity as Potential Inhibitors of the Aedes aegypti Juvenile Hormone Enzyme: A Computational Approach for Vector Mosquito Control

In silico studies on leishmanicide activity of limonoids and fatty acids from Carapa guianensis Aubl

Contact Info

Product

Resources

About