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DFT, molecular docking and molecular dynamics simulation studies on some newly introduced natural products for their potential use against SARS-CoV-2.

ABSTRACT: Throughout the history, natural products always give new paths to develop new drugs. As with many other diseases, natural compounds can be helpful in the treatment of COVID-19. SARS-CoV-2 main protease enzyme has an important role in viral replication and transcription. Therefore, inhibiting this enzyme may be helpful in the treatment of COVID-19. In this study, it is aimed to investigate eight natural compounds which have recently entered the literature, computationally for their potential use against SARS-CoV-2. For this purpose, first, density functional theory (DFT) calculations were performed on the investigated compounds, and energy minimizations, geometry optimizations, vibrational analyses, molecular electrostatic potential map calculations were carried out. After DFT calculations, geometry optimized structures were subjected to molecular docking calculations with the use of SARS-CoV-2 main protease (pdb id: 5r80) and top-scoring ligand-receptor complexes were obtained. In the next part of the study, molecular dynamics (MD) simulations were performed on the top-scoring ligand-receptor complexes to investigate the stability of the ligand-receptor complexes and the interactions between ligands and receptor in more detail. Additionally, in this part of the study, binding free energies are calculated with the use of molecular mechanics with Poisson-Boltzmann surface area (MM-PBSA) method. Results showed that, all ligand-receptor complexes remain stable during the MD simulations and most of the investigated compounds but especially two of them showed considerably high binding affinity to SARS-CoV-2 main protease. Finally, in the study, ADME (adsorption, desorption, metabolism, excretion) predictions and drug-likeness analyses were performed on the investigated compounds.

SUBMITTER: Erdogan T

PROVIDER: S-EPMC8140653 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Recent research has advocated the significant contribution of metal dyshomeostasis in developing and progressing Alzheimer's disease (AD). Disruption of homeostasis creates an imbalance of the metal ions that causes neuronal dysfunction and death. Flavonoids such as quercetin and naringenin play an essential role in iron homeostasis and are widely explored in treating various complex diseases. Iron is a critical player in many physiological activities, and hence, its homeostasis is essential for the normal functioning of the brain. Iron deficiency and iron overload contribute to AD development, highlighting the importance of maintaining iron homeostasis. Ferritin is an iron protein associated with the storage and sequestration of excess ferrous iron, playing a pivotal role in maintaining iron levels. Flavonoids are the most common polyphenolic compounds present in the human diet and are known to exert multiple neuroprotective actions. Naringenin and quercetin are extensively explored polyphenols having a broad range of therapeutic potential ranging from cancers to neurodegenerative disorders. This study aims to investigate their binding, employing molecular docking and molecular dynamics (MD) simulation in light of these polyphenols' and ferritin's therapeutic importance in AD. In this study, we performed structure-based docking of quercetin and naringenin with human ferritin. First, the binding affinity of quercetin and naringenin toward ferritin was estimated, and then their close interactions were explored to find the stable poses. All-atom 100 ns MD simulations further escorted the docking study, followed by principal component and free energy landscape analyses. The dynamic studies helped investigate the conformational dynamic, structural stability, and interaction mechanism of ferritin with quercetin and naringenin. The MD analysis suggested that the binding of quercetin and naringenin with ferritin stabilizes throughout the simulation period and leads to fewer conformational deviations. This study gives an insight at the atomistic level into the interaction between quercetin and naringenin with ferritin, thereby aiding in understanding the activity and mechanism of protein and drug binding. The study is clinically significant as iron participates in the occurrence of AD.

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DFT, molecular docking and molecular dynamics simulation studies on some newly introduced natural products for their potential use against SARS-CoV-2.

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