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INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic caused global health, economic, and population loss. Variants of the coronavirus contributed to the severity of the disease and persistent rise in infections. This study aimed to identify potential drug candidates from fifteen approved antiviral drugs against SARS-CoV-2 (6LU7), SARS-CoV (5B6O), and SARS-CoV-2 spike protein (6M0J) using virtual screening and pharmacokinetics to gain insights into COVID-19 therapeutics. METHODOLOGY: We employed drug repurposing approach to analyze binding performance of fifteen clinically approved antiviral drugs against the main protease of SARS-CoV-2 (6LU7), SARS-CoV (5B6O), and SARS-CoV-2 spike proteins bound to ACE-2 receptor (6M0J), to provide an insight into the therapeutics of COVID-19. AutoDock Vina was used for docking studies. The binding affinities were calculated, and 2-3D structures of protein-ligand interactions were drawn. RESULTS: Rutin, hesperidin, and nelfinavir are clinically approved antiviral drugs with high binding affinity to proteins 6LU7, 5B6O, and 6M0J. These ligands have excellent pharmacokinetics, ensuring efficient absorption, metabolism, excretion, and digestibility. Hesperidin showed the most potent interaction with spike protein 6M0J, forming four H-bonds. Nelfinavir had a high human intestinal absorption (HIA) score of 0.93, indicating maximum absorption in the body and promising interactions with 6LU7. CONCLUSIONS: Our results indicated that rutin, hesperidin, and nelfinavir had the highest binding results against the proposed drug targets. The computational approach effectively identified SARS-CoV-2 inhibitors. COVID-19 is still a recurrent threat globally and predictive analysis using natural compounds might serve as a starting point for new drug development against SARS-CoV-2 and related viruses.

Asunto(s)

Antivirales , COVID-19 , Reposicionamiento de Medicamentos , Simulación del Acoplamiento Molecular , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , SARS-CoV-2/efectos de los fármacos , Humanos , Antivirales/farmacocinética , Antivirales/farmacología , Antivirales/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , COVID-19/virología , Pandemias , Betacoronavirus/efectos de los fármacos , Tratamiento Farmacológico de COVID-19 , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Proteasas 3C de Coronavirus/química

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BACKGROUND: Neurodegeneration is a progressive/irreversible loss of neurons, building blocks of our nervous system. Their degeneration gradually collapses the entire structural and functional system manifesting in myriads of clinical disorders categorized as Neurodegenerative Disorders (NDs) such as Alzheimer's Disease, (AD), Parkinson's Disease (PD), Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). NDs are characterized by a puzzling interplay of molecular and cellular defects affecting subset of neuronal populations in specific affected brain areas. OBJECTIVE: In present study, comparative in silico analysis was performed by utilizing gene expression datasets of AD, PD, FTD and ALS to identify potential common features to gain insights into complex molecular pathophysiology of the selected NDs. METHODS: Gene expression data of four disorders were subjected to the identification of Differential Gene Expression (DEG) and their mapping on biological processes, KEGG pathways and molecular functions. Detailed comparative analysis was performed to highlight the common grounds of these dis-orders at various stages. RESULTS: Astoundingly, 106 DEGs were found to be common across all disorders. Alongwith in total 100 GO terms and 7 KEGG pathways were found to be significantly enriched across all disorders. EGFR, CDC42 and CREBBP have been identified as the significantly interacting nodes in gene-gene in-teraction and in Protein-Protein Interaction (PPI) network as well. Furthermore, interaction of common DEGs targets with miRNA's has been scrutinized. CONCLUSION: The complex molecular underpinnings of these disorders are currently elusive. Despite heterogeneous clinical and pathological expressions, common features have been recognized in many NDs which provide evidence of their convergence.