Structure-based drug repurposing for targeting Nsp9 replicase and spike proteins of severe acute respiratory syndrome coronavirus 2.

Drug re-purposing might be a fast and efficient way of drug development against the novel coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We applied a bioinformatics approach using molecular dynamics and docking to identify FDA-approved drugs that can be re-purposed to potentially inhibit the non-structural protein 9 (Nsp9) replicase and spike proteins in SARS-CoV-2. We performed virtual screening of FDA-approved compounds, including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis, and active phytochemicals against the Nsp9 replicase and spike proteins. Selected hit compounds were identified based on their highest binding energy and favorable absorption, distribution, metabolism and excretion (ADME) profile. Conivaptan, an arginine vasopressin antagonist drug exhibited the highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present at the active site of the Nsp9 replicase. Tegobuvir, a non-nucleoside inhibitor of the hepatitis C virus, also exhibited maximum stability along with the highest binding energy (-8.1 Kcal/mol) at the active site of the spike proteins. Molecular docking scores were further validated by molecular dynamics using Schrodinger, which supported the strong stability of ligands with the proteins at their active sites through water bridges, hydrophobic interactions, and H-bonding. Our findings suggest Conivaptan and Tegobuvir as potential therapeutic agents against SARS-CoV-2. Further in vitro and in vivo validation and evaluation are warranted to establish how these drug compounds target the Nsp9 replicase and spike proteins.

In silico identification and validation of triarylchromones as potential inhibitor against main protease of severe acute respiratory syndrome coronavirus 2.

The ongoing pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused COVID-19 has emerged as a severe threat to the life of human kind. The identification and designing of appropriate and reliable drug molecule for the treatment of COVID-19 patients is the pressing need of the present time. Among different drug targets, the main protease of SARS-CoV-2 is being considered as most effective target. In addition to the drug repurposing, different compounds of natural as well as synthetic origins are being investigated for their efficacy against different drug targets of SARS-CoV-2 virus. In that context, the chromone based natural flavonols have also exhibited significant antiviral properties against different targets of SARS-CoV-2. The in silico studies presented here discloses the efficacy of triarylchromones (TAC) as potential inhibitor against main protease of SARS-CoV-2. The molecular docking and ADMET study performed using 14 arylchromones which could easily be accessed through simple synthetic protocols, revealed best binding affinities in case of TAC-3 (-11.2 kcal/mol), TAC-4 (-10.5 kcal/mol), TAC-6 (-11.2 kcal/mol), TAC-7 (-10.0 kcal/mol). Additional validation studies including molecular dynamics simulation and binding energy calculation using MMGBSA for protein ligand complex for 100 ns revealed the best binding interaction of TAC-3, TAC-4, TAC-6, TAC-7 against main protease of SARS-CoV-2. Moreover, the in vitro and preclinical validation of identified compounds will help us to understand the molecular mechanisms of regulation of TACs against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Role of monocarboxylate transporters in head and neck squamous cell carcinoma.

Head and Neck tumors are metabolically highly altered solid tumors. Head and Neck cancer cells may utilise different metabolic pathways for energy production. Whereas, glycolysis is the major source coupled with oxidative phosphorylation in a metabolic symbiosis manner that results in the proliferation and metastasis in Head and Neck Cancer. The monocarboxylate transporters (MCTs) constitute a family of 14 members among which MCT1-4 are responsible for transporting monocarboxylates such as l-lactate and pyruvate, and ketone bodies across the plasma membrane. Additionally, MCTs mediate absorption and distribution of monocarboxylates across the cell membrane. Head and Neck cancer cells are highly glycolytic in nature and generate significant amount of lactic acid in the extracellular environment. In such condition, MCTs play a critical role in the regulation of pH, and lactate shuttle maintenance. The intracellular lactate accumulation is harmful for the cells since it drastically lowers the intracellular pH. MCTs facilitate the export of lactate out of the cell. The lactate export mediated by MCTs is crucial for the cancer cells survival. Therefore, targeting MCTs is important and could be a potential therapeutic approach to control growth of the tumor.

In silico identification of potential inhibitor for TP53-induced glycolysis and apoptosis regulator in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is the six most common cancer globally and most common cancer in men in India. The metabolic regulation is highly altered and is considered as a hall mark of HNSCC. TP53-induced glycolysis and apoptosis regulator (TIGAR) plays very important role in the development and progression of HNSCC. The aim of our study is to identify a novel FDA approved anticancer inhibitor against mutated TP53-induced glycolysis and apoptosis regulator (TIGAR) through drug repurposing approach. A library of 105 FDA approved anticancer compounds were screened using molecular docking approach against TIGAR (PDB: 3DCY) both Wild-Type (WT) and mutated (Mut). Specific mutations in TIGAR were identified using cBioPortal, a cancer genomics database and mutated structure was modelled using SWISS-MODEL. Out of 510 sequenced cases/patients samples, 17(3%) patients showed alteration in TIGAR [TIGARWT and TIGARMut (R88W)]. The virtual drug screening showed 45 drugs out of 105 high binding affinity with TIGAR, Trabectedin showed highest binding affinity with both TIGARWT (- 13.3 kcal/mol) as well as TIGARMut (R88W) (- 13.8 kcal/mol). The molecular docking studies were validated using molecular dynamics simulation (MD Simulation) of protein-ligand complex of TIGAR and Trabectedin for 100 ns. The MD Simulation of Trabectedin complex showed more stable with TIGARMut (R88W) compared to TIGARWT. Moreover, the string analysis revealed that metabolic-related genes, HK2, PFKFB1, PFKM, PFKP, PFKL, FBP1 are closely associated with TIGAR in HNSCC. Our findings suggest that Trabectedin can be proposed as an inhibitor for [TIGARMut (R88W)] which can be used to target metabolic signalings in HNSCC. However, further investigation and in vitro and in vivo validation our findings required to understand the molecular mechanisms of regulation of Trabectedin in HNSCC.

Targeting Signalling Cross-Talk between Cancer Cells and Cancer-Associated Fibroblast through Monocarboxylate Transporters in Head and Neck Cancer.

Head and Neck Squamous Cell Carcinoma (HNSCC) is an aggressive malignancy affecting more than 600,000 cases worldwide annually, associated with poor prognosis and significant morbidity. HNSCC tumors are dysplastic, with up to 80% fibroblasts. It has been reported that Cancer-Associated Fibroblasts (CAFs) facilitate HNSCC progression. Unlike normal cells, malignant cells often display increased glycolysis, even in the presence of oxygen; a phenomenon known as the Warburg effect. As a consequence, there is an increase in Lactic Acid (LA) production. Earlier, it has been reported that HNSCC tumors exhibit high LA levels that correlate with reduced survival. It has been reported that the activation of the receptor tyrosine kinase, c- MET, by CAF-secreted Hepatocyte Growth Factor (HGF) is a major contributing event in the progression of HNSCC. In nasopharyngeal carcinoma, c-MET inhibition downregulates the TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) and NADPH production resulting in apoptosis. Previously, it was demonstrated that HNSCC tumor cells are highly glycolytic. Further, CAFs show a higher capacity to utilize LA as a carbon source to fuel mitochondrial respiration than HNSCC. Earlier, we have reported that in admixed cultures, both cell types increase the expression of Monocarboxylate Transporters (MCTs) for a bidirectional LA transporter. Consequently, MCTs play an important role in signalling cross-talk between cancer cells and cancer associate fibroblast in head and neck cancer, and targeting MCTs would lead to the development of a potential therapeutic approach for head and neck cancer. In this review, we focus on the regulation of MCTs in head and neck cancer through signalling cross-talk between cancer cells and cancer-associated fibroblasts, and targeting this signalling cross talk would lead to the development of a potential therapeutic approach for head and neck cancer.

Metabolic regulation in HPV associated head and neck squamous cell carcinoma.

Cancer cells exhibit distinct energy metabolic pathways due to multiple oncogenic events. In normoxia condition, the anaerobic glycolysis (Warburg effect) is highly observed in head and neck squamous cell carcinoma (HNSCC). HNSCC is associated with smoking, chewing tobacco, consumption of alcohol or Human Papillomavirus (HPV) infection primarily HPV16. In recent years, the correlation of HPV with HNSCC has significantly expanded. Despite the recent advancement in therapeutic approaches, the rate of HPV infected HNSCC has significantly increased in the last few years, specifically, in lower middle-income countries. The oncoproteins of High-risk Human Papillomavirus (HR-HPV), E6 and E7, alter the metabolic phenotype in HNSCC, which is distinct from non-HPV associated HNSCC. These oncoproteins, modulate the cell cycle and metabolic signalling through interacting with tumor suppressor proteins, p53 and pRb. Since, metabolic alteration represents a major hallmark for tumorigenesis, HPV acts as a source of biomarker linked to cancer progression in HNSCC. The dependency of cancer cells to specific nutrients and alteration of various metabolic associated genes may provide a unique opportunity for pharmacological intervention in HPV infected HNSCC. In this review, we have discussed the molecular mechanism (s) and metabolic regulation in HNSCC depending on the HPV status. We have also discussed the possible potential therapeutic approaches for HPV associated HNSCC through targeting metabolic pathways.

Molecular mechanisms of interplay between autophagy and metabolism in cancer.

Autophagy is an essential mechanism of cellular degradation, a way to protect the cells under stress conditions, such as deprivation of nutrients, growth factors and cellular damage. However, in normal physiology autophagy plays a significant role in cancer cells. Current research is in progress to understand how autophagy and cancer cells go hand in hand to support cancer cell progression. The important aspect in cancer and autophagy is the interdependence of autophagy in the survival and progression of cancer cells. Autophagy is known to be a major cause of chemotherapeutic resistance in various cancer cell types. Therefore, inhibition of autophagy as an effective therapeutic approach is being actively studied and tested in clinical studies. Multiple metabolic pathways are linked with autophagy that could potentially be a significant target for chemotherapeutic strategy. The comprehension of the interconnection of autophagy with cancer metabolism can pave a novel findings for effective combinatorial therapeutic strategies.