In Silico Identification of Potential Inhibitors of the SARS‑CoV‑2 Nucleocapsid Through Molecular Docking‑Based Drug Repurposing

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic, and its effects on people worldwide continue to grow. Protein-targeted therapeutics are currently unavailable for this virus. As with other coronaviruses, the nucleocapsid (N) protein is the most conserved RNA-binding structural protein of SARS-CoV-2. The N protein is an appealing target because of its functional role in viral transcription and replication. Therefore, molecular docking method for structure-based drug design was used to investigate the binding energy and binding modes of various anti-N inhibitors in depth. The inhibitors selected were originally developed to target stress granules and other molecules involved in RNA biology, and were either FDA-approved or in the process of clinical trials for COVID-19. We aimed at targeting the N-terminal RNA binding domain (NTD) for molecular docking-based screening, on the basis of the first resolved crystal structure of SARS-CoV-2 N protein (PDB ID: 6M3M) and C-terminal domain (CTD) dimerization of the nucleocapsid phosphoprotein of SARS-COV-2 (PDB ID: 6WJI). Silmitasertib, nintedanib, ternatin, luteolin, and fedratinib were found to interact with RNA binding sites and to form a predicted protein interface with high binding energy. Similarly, silmitasertib, sirolimus-rapamycin, dovitinib, nintedanib, and fedratinib were found to interact with the SARS-CoV-2 N protein at its CTD dimerization sites, according to previous studies. In addition, we investigated an information gap regarding the relationships among the energetic landscape and stability and drug binding of the SARS-CoV-2 N NTD and CTD. Our in silico results clearly indicated that several tested drugs as potent putative inhibitors for COVID-19 therapeutics, thus indicating that they should be further validated as treatments to slow the spread of SARS-CoV-2

Role of NAD+ in regulating cellular and metabolic signaling pathways

BackgroundNicotinamide adenine dinucleotide (NAD+), a critical coenzyme present in every living cell, is involved in a myriad of metabolic processes associated with cellular bioenergetics. For this reason, NAD+ is often studied in the context of aging, cancer, and neurodegenerative and metabolic disorders. Scope of reviewCellular NAD+ depletion is associated with compromised adaptive cellular stress responses, impaired neuronal plasticity, impaired DNA repair, and cellular senescence. Increasing evidence has shown the efficacy of boosting NAD+ levels using NAD+ precursors in various diseases. This review provides a comprehensive understanding into the role of NAD+ in aging and other pathologies and discusses potential therapeutic targets. Major conclusionsAn alteration in the NAD+/NADH ratio or the NAD+ pool size can lead to derailment of the biological system and contribute to various neurodegenerative disorders, aging, and tumorigenesis. Due to the varied distribution of NAD+/NADH in different locations within cells, the direct role of impaired NAD+-dependent processes in humans remains unestablished. In this regard, longitudinal studies are needed to quantify NAD+ and its related metabolites. Future research should focus on measuring the fluxes through pathways associated with NAD+ synthesis and degradation

Integrative computational approach identifies drug targets in CD4+ T-cell-mediated immune disorders

CD4+ T cells provide adaptive immunity against pathogens and abnormal cells, and they are also associated with various immunerelated diseases. CD4+ T cells’ metabolism is dysregulated in these pathologies and represents an opportunity for drug discovery and development. Genome-scale metabolic modeling offers an opportunity to accelerate drug discovery by providing high-quality information about possible target space in the context of a modeled disease. Here, we develop genome-scale models of naïve, Th1, Th2, and Th17 CD4+ T-cell subtypes to map metabolic perturbations in rheumatoid arthritis, multiple sclerosis, and primary biliary cholangitis. We subjected these models to in silico simulations for drug response analysis of existing FDA-approved drugs and compounds. Integration of disease-specific differentially expressed genes with altered reactions in response to metabolic perturbations identified 68 drug targets for the three autoimmune diseases. In vitro experimental validation, together with literature-based evidence, showed that modulation of fifty percent of identified drug targets suppressed CD4+ T cells, further increasing their potential impact as therapeutic interventions. Our approach can be generalized in the context of other diseases, and the metabolic models can be further used to dissect CD4+ T-cell metabolis

Role of NADþ in regulating cellular and metabolic signaling pathways

Background: Nicotinamide adenine dinucleotide (NAD+), a critical coenzyme present in every living cell, is involved in a myriad of metabolic processes associated with cellular bioenergetics. For this reason, NAD+ is often studied in the context of aging, cancer, and neurodegenerative and metabolic disorders. Scope of review: Cellular NAD+ depletion is associated with compromised adaptive cellular stress responses, impaired neuronal plasticity, impaired DNA repair, and cellular senescence. Increasing evidence has shown the efficacy of boosting NAD+ levels using NAD+ precursors in various diseases. This review provides a comprehensive understanding into the role of NAD+ in aging and other pathologies and discusses potential therapeutic targets. Major conclusions: An alteration in the NAD+/NADH ratio or the NAD+ pool size can lead to derailment of the biological system and contribute to various neurodegenerative disorders, aging, and tumorigenesis. Due to the varied distribution of NAD+/NADH in different locations within cells, the direct role of impaired NAD+-dependent processes in humans remains unestablished. In this regard, longitudinal studies are needed to quantify NAD+ and its related metabolites. Future research should focus on measuring the fluxes through pathways associated with NAD+synthesis and degradation. Background: Nicotinamide adenine dinucleotide (NAD+), a critical coenzyme present in every living cell, is involved in a myriad of metabolic processes associated with cellular bioenergetics. For this reason, NAD+ is often studied in the context of aging, cancer, and neurodegenerative and metabolic disorders. Scope of review: Cellular NAD+ depletion is associated with compromised adaptive cellular stress responses, impaired neuronal plasticity, impaired DNA repair, and cellular senescence. Increasing evidence has shown the efficacy of boosting NAD+ levels using NAD+ precursors in various diseases. This review provides a comprehensive understanding into the role of NAD+ in aging and other pathologies and discusses potential therapeutic targets. Major conclusions: An alteration in the NAD+/NADH ratio or the NAD+ pool size can lead to derailment of the biological system and contribute to various neurodegenerative disorders, aging, and tumorigenesis. Due to the varied distribution of NAD+/NADH in different locations within cells, the direct role of impaired NAD+-dependent processes in humans remains unestablished. In this regard, longitudinal studies are needed to quantify NAD+ and its related metabolites. Future research should focus on measuring the fluxes through pathways associated with NAD+ synthesis and degradation

Integrative computational approach identifies drug targets in CD4 + T-cell-mediated immune disorders

CD4+ T cells provide adaptive immunity against pathogens and abnormal cells, and they are also associated with various immune-related diseases. CD4+ T cells’ metabolism is dysregulated in these pathologies and represents an opportunity for drug discovery and development. Genome-scale metabolic modeling offers an opportunity to accelerate drug discovery by providing high-quality information about possible target space in the context of a modeled disease. Here, we develop genome-scale models of naïve, Th1, Th2, and Th17 CD4+ T-cell subtypes to map metabolic perturbations in rheumatoid arthritis, multiple sclerosis, and primary biliary cholangitis. We subjected these models to in silico simulations for drug response analysis of existing FDA-approved drugs and compounds. Integration of disease-specific differentially expressed genes with altered reactions in response to metabolic perturbations identified 68 drug targets for the three autoimmune diseases. In vitro experimental validation, together with literature-based evidence, showed that modulation of fifty percent of identified drug targets suppressed CD4+ T cells, further increasing their potential impact as therapeutic interventions. Our approach can be generalized in the context of other diseases, and the metabolic models can be further used to dissect CD4+ T-cell metabolism