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BACKGROUND: Oral cancer poses a significant threat to public health worldwide. In addition, because many chemotherapy treatments have negative side effects, natural herbs may be beneficial for oral cancer therapy. Achyranthes aspera (AA), a potential medicinal herb, exerts various pharmacological and biochemical activities. OBJECTIVE: The present study aimed to predict the anti-oral cancer potential of AA using in silico tools and cell death by in vitro testing. METHODS: A total of fourteen bioactive constituents from AA herb were selected using phytochemical databases. The toxicity of AA herb extract was analysed through MTT assay against oral carcinoma A253 cell line. The binding activities of the phytocomponents against serine/ threonine-specific protein kinases isoforms, namely Akt1 (PDB ID: 3qkk) and Akt2 (PDB ID: 2jdo) proteins, were analysed using Discovery Studio 2021 and PyRx docking software. RESULTS: Cell viability data revealed that AA extract decreased the viability and reduced the number of live cells of the oral carcinoma A253 cell line in a dose-dependent manner. The halfmaximal concentration (IC50) value of AA was assessed as 204.74 µg/ml. Based on binding affinity, saponin C (-CDOCKER energy = -77.9862), oleanolic acid (-CDOCKER energy = - 49.4349), spinasterol (-CDOCKER energy = -38.1246), 36,47-dihydroxyhenpentacontan-4-one (-CDOCKER energy = -32.4386), and 20-hydroxyecdysone (-CDOCKER energy = -31.9138) were identified as the best compounds against Akt1, while, compounds saponin C (-CDOCKER energy = -134.412), oleanolic acid (-CDOCKER energy = -90.0846), spinasterol (-CDOCKER energy = -78.3213), 20-hydroxyecdysone (-CDOCKER energy = -80.1049), and ecdysone (- CDOCKER energy = -73.3885) were identified as Akt2 inhibitors. These top compounds fulfilled drug score values, pharmacokinetic and physicochemical characteristics, and druglikeness parameters. CONCLUSION: The present findings reveal that the lead phytomolecules of AA could be effective and developed as a prospective drug against oral cancer.
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Major significant advancements in pharmacology and drug technology have been made to heighten the impact of cancer therapies, improving the life expectancy of subjects diagnosed with malignancy. Statistically, 99% of breast cancers occur in women while 0.5-1% occur in men, the female gender being the strongest breast cancer risk factor. Despite several breakthroughs, breast cancer continues to have a worldwide impact and is one of the leading causes of mortality. Additionally, resistance to therapy is a crucial factor enabling cancer cell persistence and resurgence. As a result, the search and discovery of novel modulatory agents and effective therapies capable of controlling tumor progression and cancer cell proliferation is critical. Withania somnifera (L.) Dunal (WS), commonly known as Indian ginseng, has long been used traditionally for the treatment of several ailments in the Indian context. Recently, WS and its phytoconstituents have shown promising anti-breast cancer properties and, as such, can be employed as prophylactic as well as therapeutic adjuncts to the main line of breast cancer treatment. The present review is an attempt to explore and provide experimental evidences in support of the prophylactic and therapeutic potential of WS in breast cancer, along with a deeper insight into the multiple molecular mechanisms and novel targets through which it acts against breast and other hormonally-induced cancers viz. ovarian, uterine and cervical. This exploration might prove crucial in providing better understanding of breast cancer progression and metastasis and its use as an adjunct in improving disease prognosis and therapeutic outcome.
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Neoplasias de la Mama , Extractos Vegetales , Withania , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Withania/química , Femenino , Animales , Extractos Vegetales/uso terapéutico , Extractos Vegetales/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos Fitogénicos/farmacología , FitoterapiaRESUMEN
Prevention from disease is presently the cornerstone of the fight against COVID-19. With the rapid emergence of novel SARS-CoV-2 variants, there is an urgent need for novel or repurposed agents to strengthen and fortify the immune system. Existing vaccines induce several systemic and local side-effects that can lead to severe consequences. Moreover, elevated cytokines in COVID-19 patients with cancer as co-morbidity represent a significant bottleneck in disease prognosis and therapy. Withania somnifera (WS) and its phytoconstituent(s) have immense untapped immunomodulatory and therapeutic potential and the anticancer potential of WS is well documented. To this effect, WS methanolic extract (WSME) was characterized using HPLC. Withanolides were identified as the major phytoconstituents. In vitro cytotoxicity of WSME was determined against human breast MDA-MB-231 and normal Vero cells using MTT assay. WSME displayed potent cytotoxicity against MDA-MB-231 cells (IC50: 66 µg/mL) and no effect on Vero cells in the above range. MD simulations of Withanolide A with SARS-CoV-2 main protease and spike receptor-binding domain as well as Withanolide B with SARS-CoV spike glycoprotein and SARS-CoV-2 papain-like protease were performed using Schrödinger. Stability of complexes followed the order 6M0J-Withanolide A > 6W9C-Withnaolide B > 5WRG-Withanolide B > 6LU7-Withanolide A. Maximum stable interaction(s) were observed between Withanolides A and B with SARS-CoV-2 and SARS-CoV spike glycoproteins, respectively. Withanolides A and B also displayed potent binding to pro-inflammatory markers viz. serum ferritin and IL-6. Thus, WS phytoconstituents have the potential to be tested further in vitro and in vivo as novel antiviral agents against COVID-19 patients having cancer as a co-morbidity. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00184-y.
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Lectins are non-immunological carbohydrate-binding proteins classified on the basis of their structure, origin, and sugar specificity. The binding specificity of such proteins with the surface glycan moiety determines their activity and clinical applications. Thus, lectins hold great potential as diagnostic and drug discovery agents and as novel biopharmaceutical products. In recent years, significant advancements have been made in understanding plant and microbial lectins as therapeutic agents against various viral diseases. Among them, mannose-specific lectins have being proven as promising antiviral agents against a variety of viruses, such as HIV, Influenza, Herpes, Ebola, Hepatitis, Severe Acute Respiratory Syndrome Coronavirus-1 (SARS-CoV-1), Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV) and most recent Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The binding of mannose-binding lectins (MBLs) from plants and microbes to high-mannose containing N-glycans (which may be simple or complex) of glycoproteins found on the surface of viruses has been found to be highly specific and mainly responsible for their antiviral activity. MBLs target various steps in the viral life cycle, including viral attachment, entry and replication. The present review discusses the brief classification and structure of lectins along with antiviral activity of various mannose-specific lectins from plants and microbial sources and their diagnostic and therapeutic applications against viral diseases.
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Lectinas , Virosis , Humanos , Lectinas/metabolismo , Manosa , Glicoproteínas , SARS-CoV-2 , Polisacáridos , Antivirales/farmacología , Antivirales/uso terapéutico , Antivirales/química , Virosis/tratamiento farmacológico , Lectinas de Plantas/farmacología , Lectinas de Unión a Manosa/químicaRESUMEN
Good nutrition plays a crucial role in maintaining a balanced lifestyle. The beneficial effects of nutrition have been found to counteract nutritional disturbances with the expanded use of nutraceuticals to treat and manage cardiovascular diseases, cancer, and other developmental defects over the last decade. Flavonoids are found abundantly in plant-derived foods such as fruits, vegetables, tea, cocoa, and wine. Fruits and vegetables contain phytochemicals like flavonoids, phenolics, alkaloids, saponins, and terpenoids. Flavonoids can act as anti-inflammatory, anti-allergic, anti-microbial (antibacterial, antifungal, and antiviral) antioxidant, anti-cancer, and anti-diarrheal agents. Flavonoids are also reported to upregulate apoptotic activity in several cancers such as hepatic, pancreatic, breast, esophageal, and colon. Myricetin is a flavonol which is naturally present in fruits and vegetables and has shown possible nutraceutical value. Myricetin has been portrayed as a potent nutraceutical that may protect against cancer. The focus of the present review is to present an updated account of studies demonstrating the anticancer potential of myricetin and the molecular mechanisms involved therein. A better understanding of the molecular mechanism(s) underlying its anticancer activity would eventually help in its development as a novel anticancer nutraceutical having minimal side effects.
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Antineoplásicos , Neoplasias , Humanos , Flavonoides/farmacología , Flavonoides/uso terapéutico , Flavonoides/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Suplementos Dietéticos , Antioxidantes/farmacología , Neoplasias/tratamiento farmacológicoRESUMEN
A global hazard to public health has been generated by the coronavirus infection 2019 (COVID-19), which is spreading quickly. Pomegranate is a strong source of antioxidants and has demonstrated a number of pharmacological characteristics. This work was aimed to analyze the phytochemicals present in ethanolic pomegranate seed extract (PSE) and their in vitro antioxidant potential and further in-silico evaluation for antiviral potential against crystal structure of two nucleocapsid proteins i.e., N-terminal RNA binding domain (NRBD) and C-terminal Domain (CTD) of SARS-CoV-2. The bioactive components from ethanolic extract of PSE were assessed by gas chromatography-mass spectroscopy (GC-MS). Free radical scavenging activity of PSE was determined using DPPH dye. Molecular docking was executed through the Glide module of Maestro software. Lipinski's 5 rule was applied for drug-likeness characteristics using cheminformatics Molinspiration software while OSIRIS Data Warrior V5.5.0 was used to predict possible toxicological characteristics of components. Thirty-two phytocomponents was detected in PSE by GC-MS technique. Free radical scavenging assay revealed the high antioxidant capacity of PSE. Docking analysis showed that twenty phytocomponents from PSE exhibited good binding affinity (Docking score ≥ - 1.0 kcal/mol) towards NRBD and CTD nucleocapsid protein. This result increases the possibility that the top 20 hits could prevent the spread of SARS-CoV-2 by concentrating on both nucleocapsid proteins. Moreover, molecular dynamics (MD) simulation using GROMACS was used to check their binding efficacy and internal dynamics of top complexes with the lowest docking scores. The metrics root mean square deviation (RMSD), root mean square fluctuation (RMSF), intermolecular hydrogen bonding (H-bonds) and radius of gyration (Rg) revealed that the lead phytochemicals form an energetically stable complex with the target protein. Majority of the phytoconstituents exhibited drug-likeness with non-tumorigenic properties. Thus, the PSE phytoconstituents could be useful source of drug or nutraceutical development in SARS-CoV-2 pathogenesis.
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COVID-19 , Granada (Fruta) , Antioxidantes/farmacología , Simulación del Acoplamiento Molecular , SARS-CoV-2 , Etanol , Simulación de Dinámica Molecular , Proteínas de la Nucleocápside , Radicales LibresRESUMEN
BACKGROUND: Breast cancer is the world's most prevalent cancer among women. Microorganisms have been the richest source of antibiotics as well as anticancer drugs. Moricin peptides have shown antibacterial properties; however, the anticancer potential and mechanistic insights into moricin peptide-induced cancer cell death have not yet been explored. METHODS: An investigation through in silico analysis, analytical methods (Reverse Phase-High Performance Liquid Chromatography (RP-HPLC), mass spectroscopy (MS), circular dichroism (CD), and in vitro studies, has been carried out to delineate the mechanism(s) of moricin-induced cancer cell death. An in-silico analysis was performed to predict the anticancer potential of moricin in cancer cells using Anti CP and ACP servers based on a support vector machine (SVM). Molecular docking was performed to predict the binding interaction between moricin and peptide-related cancer signaling pathway(s) through the HawkDOCK web server. Further, in vitro anticancer activity of moricin was performed against MDA-MB-231 cells. RESULTS: In silico observation revealed that moricin is a potential anticancer peptide, and protein-protein docking showed a strong binding interaction between moricin and signaling proteins. CD showed a predominant helical structure of moricin, and the MS result determined the observed molecular weight of moricin is 4544 Da. An in vitro study showed that moricin exposure to MDA-MB-231 cells caused dose dependent inhibition of cell viability with a high generation of reactive oxygen species (ROS). Molecular study revealed that moricin exposure caused downregulation in the expression of Notch-1, NF-ÆB and Bcl2 proteins while upregulating p53, Bax, caspase 3, and caspase 9, which results in caspase-dependent cell death in MDA-MB-231 cells. CONCLUSIONS: In conclusion, this study reveals the anticancer potential and underlying mechanism of moricin peptide-induced cell death in triple negative cancer cells, which could be used in the development of an anticancer drug.
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The global malnutrition burden imparts long-term developmental, economic, social, and medical consequences to individuals, communities, and countries. The current developments in biotechnology have infused biofortification in several food crops to fight malnutrition. However, these methods are not sustainable and suffer from several limitations, which are being solved by the CRISPR-Cas-based system of genome editing. The pin-pointed approach of CRISPR-based genome editing has made it a top-notch method due to targeted gene editing, thus making it free from ethical issues faced by transgenic crops. The CRISPR-Cas genome-editing tool has been extensively used in crop improvement programs due to its more straightforward design, low methodology cost, high efficiency, good reproducibility, and quick cycle. The system is now being utilized in the biofortification of cereal crops such as rice, wheat, barley, and maize, including vegetable crops such as potato and tomato. The CRISPR-Cas-based crop genome editing has been utilized in imparting/producing qualitative enhancement in aroma, shelf life, sweetness, and quantitative improvement in starch, protein, gamma-aminobutyric acid (GABA), oleic acid, anthocyanin, phytic acid, gluten, and steroidal glycoalkaloid contents. Some varieties have even been modified to become disease and stress-resistant. Thus, the present review critically discusses CRISPR-Cas genome editing-based biofortification of crops for imparting nutraceutical properties.
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Lead (Pb) is found in almost all phases in environment and biological systems. Pb stimulated oxidative stress is a state that involves the generation of free radicals beyond the permissible limits, which can deplete the antioxidant reserves and can result in oxidative stress, thus hampering the ability of the biological system to reverse the result. Exposure of rats to Pb (25 mg/kg body weight) for 8 weeks caused an increase in Pb levels in blood and brain. Activity of delta-aminolevulinic acid dehydratase (δ-ALAD) and antioxidant enzymes such as Superoxide dismutase (SOD) and Catalase (CAT) decreased in the blood of Pb-treated group with a concomitant increase in the level of lipid peroxidation (LPO) and no significant change in the level of reduced glutathione (GSH) level was found. Interestingly, co-treatment of Pb-treated rats with curcumin (30 mg/kg body weight) and quercetin (30 mg/kg body weight) for 8 weeks caused a significant decrease in Pb levels of blood and all brain regions versus those treated with Pb alone. A significant improvement in levels of MDA, δ-ALAD, SOD and CAT activities was observed in rats simultaneously treated with curcumin or Quercetin or both with lead. Therefore, the ameliorative impact of curcumin and Quercetin might be due to their antioxidant property hence were able to counter the oxidative stress generated by Pb. These results suggest that combination of curcumin and Quercetin could be utilized as a possible supplement with the relevant therapeutics in the suitable management of Pb toxicity.
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Novel SARS-CoV-2 claimed a large number of human lives. The main proteins for viral entry into host cells are SARS-CoV-2 spike glycoprotein (PDB ID: 6VYB) and spike receptor-binding domain bound with ACE2 (spike RBD-ACE2; PDB ID: 6M0J). Currently, specific therapies are lacking globally. This study was designed to investigate the bioactive components from Moringa oleifera leaf (MOL) extract by gas chromatography-mass spectroscopy (GC-MS) and their binding interactions with spike glycoprotein and spike RBD-ACE2 protein through computational analysis. GC-MS-based analysis unveiled the presence of thirty-seven bioactive components in MOL extract, viz. polyphenols, fatty acids, terpenes/triterpenes, phytosterols/steroids, and aliphatic hydrocarbons. These bioactive phytoconstituents showed potential binding with SARS-CoV-2 spike glycoprotein and spike RBD-ACE2 protein through the AutoDock 4.2 tool. Further by using AutoDock 4.2 and AutoDock Vina, the top sixteen hits (binding energy ≥ - 6.0 kcal/mol) were selected, and these might be considered as active biomolecules. Moreover, molecular dynamics simulation was determined by the Desmond module. Interestingly two biomolecules, namely ß-tocopherol with spike glycoprotein and ß-sitosterol with spike RBD-ACE2, displayed the best interacting complexes and low deviations during 100-ns simulation, implying their strong stability and compactness. Remarkably, both ß-tocopherol and ß-sitosterol also showed the drug- likeness with no predicted toxicity. In conclusion, these findings suggested that both compounds ß-tocopherol and ß-sitosterol may be developed as anti-SARS-CoV-2 drugs. The current findings of in silico approach need to be optimized using in vitro and clinical studies to prove the effectiveness of phytomolecules against SARS-CoV-2.
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Tratamiento Farmacológico de COVID-19 , Moringa oleifera , Humanos , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2 , beta-Tocoferol , Fitoquímicos/farmacología , Hojas de la Planta , Simulación de Dinámica Molecular , Extractos Vegetales/farmacología , Unión ProteicaRESUMEN
SARS-CoV-2 has been responsible for causing 6,218,308 deaths globally till date and has garnered worldwide attention. The lack of effective preventive and therapeutic drugs against SARS-CoV-2 has further worsened the scenario and has bolstered research in the area. The N-terminal and C-terminal RNA binding domains (NTD and CTD) of SARS-CoV-2 nucleocapsid protein represent attractive therapeutic drug targets. Naturally occurring compounds are an excellent source of novel drug candidates due to their structural diversity and safety. Ten major bioactive compounds were identified in ethanolic extract (s) of Cinnamomum zeylanicum, Cinnamomum tamala, Origanum vulgare, and Petroselinum crispum using HPLC and their cytotoxic potential was determined against cancer and normal cell lines by MTT assay to ascertain their biological activity in vitro. To evaluate their antiviral potential, the binding efficacy to NTD and CTD of SARS-CoV-2 nucleocapsid protein was determined using in silico biology tools. In silico assessment of the phytocomponents revealed that most of the phytoconstituents displayed a druglike character with no predicted toxicity. Binding affinities were in the order apigenin > catechin > apiin toward SARS-CoV-2 nucleocapsid NTD. Toward nucleocapsid CTD, the affinity decreased as apigenin > cinnamic acid > catechin. Remdesivir displayed lesser affinity with NTD and CTD of SARS-CoV-2 nucleocapsid proteins than any of the studied phytoconstituents. Molecular dynamics (MD) simulation results revealed that throughout the 100 ns simulation, SARS-CoV-2 nucleocapsid protein NTD-apigenin complex displayed greater stability than SARS-CoV-2 nucleocapsid protein NTD-cinnamic acid complex. Hence, apigenin, catechin, apiin and cinnamic acid might prove as effective prophylactic and therapeutic candidates against SARS-CoV-2, if examined further in vitro and in vivo. PRACTICAL APPLICATIONS: Ten major bioactive compounds were identified in the extract(s) of four medicinally important plants viz. Cinnamomum zeylanicum, Cinnamomum tamala, Origanum vulgare and Petroselinum crispum using HPLC and their biological activity was also evaluated against cancer and normal cell lines. Interestingly, while all extract(s) wielded significant cytotoxicity against cancer cells, no significant toxicity was found against normal cells. The outcome of the results prompted evaluation of the antiviral potential of the ten bioactive compounds using in silico biology tools. The present study emphasizes on the application of computational approaches to understand the binding interaction and efficacy of the ten bioactive compounds from the above plants with SARS-CoV-2 nucleocapsid protein N-terminal and C-terminal RNA binding domains in preventing and/or treating COVID-19 using in silico tools. Druglikeness and toxicity profiles of the compounds were carried out to check the therapeutic application of the components. Additionally, molecular dynamics (MD) simulation was performed to check the stability of ligand-protein complexes. The results provided useful insights into the structural binding interaction(s) that can be exploited for the further development of potential antiviral agents targeting SARS-CoV-2 especially since no specific therapy is still available to combat the rapidly evolving virus and the existing treatment is more or less symptomatic which makes search for novel antiviral agents all the more necessary and crucial.
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Tratamiento Farmacológico de COVID-19 , Catequina , Laurus , Origanum , Antivirales/química , Antivirales/farmacología , Apigenina , Cinamatos , Cinnamomum zeylanicum/metabolismo , Suplementos Dietéticos , Laurus/metabolismo , Ligandos , Petroselinum/metabolismo , SARS-CoV-2RESUMEN
BACKGROUND: Phoenix dactylifera L. has a diverse set of pharmacological properties due to its distinct phytochemical profile. The purpose of this study was to investigate the anticancer potential of Phoenix dactylifera seed extract (PDSE) in human breast cancer MDA-MB-231 and MCF-7 cells, as well as liver cancer HepG2 cells, and to investigate the anticancer efficacy in triple-negative MDA-MB-231 cells, followed by in silico validation of the molecular interaction between active components of PDSE and caspase-3, an apoptosis executioner protein . METHODS: In this study, human cancer cell lines were cultured and subsequently treated with 10 to 100 µg/mL of PDSE. MTT test was performed to determine the cell viability, MMP was measured using fluorescent probe JC-1, nuclear condensation was determined by Hoechst 33258 dye, Annexin V-FITC & PI staining and cell cycle analysis were evaluated through flow cytometer, and apoptotic markers were detected using western blotting. The bioactive agents in PDSE were identified using high-performance liquid chromatography (HPLC) analysis. The binding affinity was validated using molecular docking tools AutoDock Vina and iGEMDOCK v2.1. RESULTS: Cell viability data indicated that PDSE inhibited cell proliferation in both breast cancer cells and liver cancer cells. MDA-MB-231 cells showed maximum growth inhibition with an IC50 value of 85.86 µg/mL for PDSE. However, PDSE did not show any significant toxicity against the normal Vero cell line. PDSE induced MMP loss and formation of apoptotic bodies, enhanced late apoptosis at high doses and arrested cells in the S phase of cell cycle. PDSE activated the enzymatic activity of cleaved caspase-3 and caused the cleavage of poly-ADB ribose polymerase (PARP) protein. PDSE upregulated pro-apoptotic Bax protein markedly but no significant effect on tumor suppressor protein p53, while it downregulated the anti-apoptotic Bcl-2 protein expression. HPLC analysis showed the presence of rutin and quercetin bioactive flavonols in ethanolic extract of PDS. Interestingly, both active components revealed a strong binding interaction with amino acid residues of caspase-3 (PDB ID: 2XYP; Hetero 4-mer - A2B2) protein. CONCLUSION: PDS could serve as a potential medicinal source for apoptotic cell death in human breast cancer cells and, thus, could be used as a promising and crucial candidate in anticancer drug development. This study warrants further in vivo research, followed by clinical investigation.
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Neoplasias de la Mama , Phoeniceae , Neoplasias de la Mama/tratamiento farmacológico , Caspasa 3/metabolismo , Línea Celular Tumoral , Femenino , Humanos , Simulación del Acoplamiento Molecular , Phoeniceae/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
Therapeutic drugs based on natural products for the treatment of SARS-CoV-2 are currently unavailable. This study was conducted to develop an anti-SARS-CoV-2 herbal medicine to face the urgent need for COVID-19 treatment. The bioactive components from ethanolic extract of Moringa oleifera fruits (MOFs) were determined by gas chromatography-mass spectroscopy (GC-MS). Molecular-docking analyses elucidated the binding effects of identified phytocomponents against SARS-CoV-2 spike glycoprotein (PDB ID: 6VYB) and human ACE2 receptor (PDB ID: 1R42) through the Glide module of Maestro software. GC-MS analysis unveiled the presence of 33 phytocomponents. Eighteen phytocomponents exhibited good binding affinity toward ACE2 receptor, and thirteen phytocomponents had a high affinity with spike glycoprotein. This finding suggests that the top 11 hits (Docking score ≥ -3.0 kcal/mol) could inhibit SARS-CoV-2 propagation. Intriguingly, most of the phytoconstituents displayed drug-likeness with no predicted toxicity. However, further studies are needed to validate their effects and mechanisms of action. PRACTICAL APPLICATIONS: Moringa oleifera (MO) also called "drumstick tree" has been used as an alternative food source to combat malnutrition and may act as an immune booster. GC-MS analysis unveiled that ethanolic extract of Moringa oleifera fruits (MOFs) possessed 33 active components of pyridine, aromatic fatty acid, oleic acid, tocopherol, methyl ester, diterpene alcohol, triterpene and fatty acid ester and their derivatives, which have various pharmacological and medicinal values. Virtual screening study of phytocomponents of MOF with human ACE2 receptor and SARS-CoV-2 spike glycoprotein exhibited good binding affinity. Based on molecular docking, the top 11 hits (Docking score ≥-3.0 kcal/mol) might serve as potential lead molecules in antiviral drug development. Intriguingly, most of the phytoconstituents displayed drug-likeness with no predicted toxicity. Thus, MOF might be used as a valuable source for antiviral drug development to combat COVID-19, an ongoing pandemic.
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Antivirales , Moringa oleifera , Extractos Vegetales , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2 , Antivirales/química , Antivirales/farmacología , Ésteres/farmacología , Ácidos Grasos/farmacología , Frutas/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Moringa oleifera/química , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , SARS-CoV-2/efectos de los fármacos , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/farmacología , Tratamiento Farmacológico de COVID-19RESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel etiological agent of coronavirus disease 2019 (COVID-19). Nigella sativa, commonly known as black seed or black cumin, has been a historical and traditional plant since thousands of years. Based on their therapeutic efficacy, the chief components of terpenoids and flavonoids were selected from N. sativa seeds and seed oil. This study was designed to check the antiviral efficacy of N. sativa main phytoconstituents against five potential targets of SARS-CoV-2 using in silico structure-based virtual screening approach. Out of twenty five phytocomponents, ten components showed best binding affinity against two viral proteins viz. N-terminal RNA binding domain (NRBD; PDB ID: 6M3M) of nucleocapsid protein and papain-like protease (PL-PRO; PDB ID: 6W9C) of SARS-CoV-2 using AutoDock 4.2.6, AutoDock Vina and iGEMDOCK. PASS analyses of all ten phytocomponents using Lipinski's Rule of five showed promising results. Further, druglikeness and toxicity assessment using OSIRIS Data Warrior v5.2.1 software exhibited the feasibility of phytocomponents as drug candidates with no predicted toxicity. Molecular dynamics simulation study of NRBD of SARS-CoV-2 nucleocapsid protein-alpha-spinasterol complex and PL-PRO-cycloeucalenol complex displayed strong stability at 300 K. Both these complexes exhibited constant root mean square deviation (RMSDs) of protein side chains and Cα atoms throughout the simulation run time. Interestingly, PL-PRO and NRBD are key proteins in viral replication, host cell immune evasion and viral assembly. Thus, NRBD and PL-PRO have the potential to serve as therapeutic targets for N. sativa phytoconstituents in drug discovery process against COVID-19.
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Antivirales , Proteínas de la Nucleocápside de Coronavirus , Proteasas Similares a la Papaína de Coronavirus , Nigella sativa , SARS-CoV-2 , Antivirales/química , Proteínas de la Nucleocápside de Coronavirus/antagonistas & inhibidores , Proteasas Similares a la Papaína de Coronavirus/antagonistas & inhibidores , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Nigella sativa/química , Fosfoproteínas/antagonistas & inhibidores , Inhibidores de Proteasas/química , SARS-CoV-2/efectos de los fármacos , Tratamiento Farmacológico de COVID-19RESUMEN
A sudden outbreak of a novel coronavirus SARS-CoV-2 in 2019 has now emerged as a pandemic threatening to efface the existence of mankind. In absence of any valid and appropriate vaccines to combat this newly evolved agent, there is need of novel resource molecules for treatment and prophylaxis. To this effect, flavonol morin which is found in fruits, vegetables and various medicinal herbs has been evaluated for its antiviral potential in the present study. PASS analysis of morin versus reference antiviral drugs baricitinib, remdesivir and hydroxychloroquine revealed that morin displayed no violations of Lipinski's rule of five and other druglikeness filters. Morin also displayed no tumorigenic, reproductive or irritant effects and exhibited good absorption and permeation through GI (clogP <5). In principal component analysis, morin appeared closest to baricitinib in 3D space. Morin displayed potent binding to spike glycoprotein, main protease 3CLPro and papain-like protease PLPro of SARS-CoV-2, SARS-CoV and MERS-CoV using molecular docking and significant binding to three viral-specific host proteins viz. human ACE2, importin-α and poly (ADP-ribose) polymerase (PARP)-1, further lending support to its antiviral efficacy. Additionally, morin displayed potent binding to pro-inflammatory cytokines IL-6, 8 and 10 also supporting its anti-inflammatory activity. MD simulation of morin with SARS-CoV-2 3CLPro and PLPro displayed strong stability at 300 K. Both complexes exhibited constant RMSDs of protein side chains and Cα atoms throughout the simulation run time. In conclusion, morin might hold considerable therapeutic potential for the treatment and management of not only COVID-19, but also SARS and MERS if studied further. Communicated by Ramaswamy H. Sarma.
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Tratamiento Farmacológico de COVID-19 , Coronavirus del Síndrome Respiratorio de Oriente Medio , Humanos , Enzima Convertidora de Angiotensina 2 , Antivirales/química , Flavonoides , Flavonoles , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Poli(ADP-Ribosa) Polimerasas , SARS-CoV-2 , Proteínas Virales/químicaRESUMEN
There is currently a dearth of specific therapies to treat respiratory infections caused by the three related species of coronaviruses viz. SARS-CoV-2, SARS-CoV and MERS-CoV. Prevention from disease is currently the safest and most convenient alternative available. The present study aimed to evaluate the preventive and therapeutic effect of fifteen phytoconstituents from medicinal plants of Ayurveda against coronaviruses by in silico screening. All the phytoconstituents exhibited rapid GI absorption and bioavailability and most of them had no toxicity versus reference drug chloroquine. BAS analyses revealed that most of the phytocomponents had favorable bioactivity scores towards biological target proteins. Principal component analysis revealed that most of the phytoconstituents fell close to chloroquine in 3D projection of chemical space. Affinity of phytoconstituents towards SARS-CoV-2 spike protein-human ACE2 complex decreased as isomeldenin > tinosporaside > EGCG whereas in case of unbound ACE2, the strength of binding followed the order isomeldenin > tinosporaside > ellagic acid. Towards SARS-CoV-2 main and papain-like proteases, the affinity decreased as isomeldenin > EGCG > tinosporaside and EGCG > tinosporaside > isomeldenin, respectively. Most phytoconstituents displayed significant binding kinetics to the selected protein targets than chloroquine. SAR analysis revealed that isomeldenin, tinosporaside, EGCG and ellagic acid bind to viral spike glycoproteins via H-bond, Pi-Pi, Pi-sigma and Pi-alkyl type interactions. Molecular dynamics simulation of isomeldenin and EGCG with SARS-CoV and SARS-CoV-2 spike glycoproteins exhibited low deviations throughout the 100 ns simulation indicating good stability and compactness of the protein-ligand complexes. Thus, the above four phytoconstituents have the potential to emerge as prophylactic and therapeutic agents against coronaviruses if investigated further in vitro and in vivo.
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Antivirales , Medicina Ayurvédica , SARS-CoV-2 , Humanos , Enzima Convertidora de Angiotensina 2/química , Antivirales/química , Cloroquina/metabolismo , COVID-19 , Ácido Elágico/metabolismo , Glicoproteínas/metabolismo , Agentes Inmunomoduladores , Simulación del Acoplamiento Molecular , SARS-CoV-2/efectos de los fármacos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacosRESUMEN
Coronaviruses are etiological agents of extreme human and animal infection resulting in abnormalities primarily in the respiratory tract. Presently, there is no defined COVID-19 intervention and clinical trials of prospective therapeutic agents are still in the nascent stage. Withania somnifera (L.) Dunal (WS), is an important medicinal plant in Ayurveda. The present study aimed to evaluate the antiviral potential of selected WS phytoconstituents against the novel SARS-CoV-2 target proteins and human ACE2 receptor using in silico methods. Most of the phytoconstituents displayed good absorption and transport kinetics and were also found to display no associated mutagenic or adverse effect(s). Molecular docking analyses revealed that most of the WS phytoconstituents exhibited potent binding to human ACE2 receptor, SAR-CoV and SARS-CoV-2 spike glycoproteins as well as the two main SARS-CoV-2 proteases. Most of the phytoconstituents were predicted to undergo Phase-I metabolism prior to excretion. All phytoconstituents had favorable bioactivity scores with respect to various receptor proteins and target enzymes. SAR analysis revealed that the number of oxygen atoms in the withanolide backbone and structural rearrangements were crucial for effective binding. Molecular simulation analyses of SARS-CoV-2 spike protein and papain-like protease with Withanolides A and B, respectively, displayed a stability profile at 300 K and constant RMSDs of protein side chains and Cα atoms throughout the simulation run time. In a nutshell, WS phytoconstituents warrant further investigations in vitro and in vivo to unravel their molecular mechanism(s) and modes of action for their future development as novel antiviral agents against COVID-19.
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COVID-19 , Withania , Animales , Antivirales/química , Antivirales/farmacología , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Withania/químicaRESUMEN
Ajwa dates (Phoenix dactylifera L.) have been described in traditional and alternative medicine to provide several health benefits, but their mechanism of apoptosis induction against human triple-negative breast cancer MDA-MB-231 cells remains to be investigated. In this study, we analyzed the phytoconstituents in ethanolic Ajwa Dates Pulp Extract (ADPE) by liquid chromatography-mass spectrometry (LC-MS) and investigated anticancer effects against MDA-MB-231 cells. LC-MS analysis revealed that ADPE contained phytocomponents belonging to classes such as carbohydrates, phenolics, flavonoids and terpenoids. MTT assay demonstrated statistically significant dose- and time-dependent inhibition of MDA-MB-231 cells with IC50 values of 17.45 and 16.67 mg/mL at 24 and 48 h, respectively. Hoechst 33342 dye and DNA fragmentation data showed apoptotic cell death while AO/PI and Annexin V-FITC data revealed cells in late apoptosis at higher doses of ADPE. More importantly, ADPE prompted reactive oxygen species (ROS) induced alterations in mitochondrial membrane potential (MMP) in ADPE treated MDA-MB-231 cells. Cell cycle analysis demonstrated that ADPE induced cell arrest in S and G2/M checkpoints. ADPE upregulated the p53, Bax and cleaved caspase-3, thereby leading to the downregulation of Bcl-2 and AKT/mTOR pathway. ADPE did not show any significant toxicity on normal human peripheral blood mononuclear cells which suggests its safe application to biological systems under study. Thus, ADPE has the potential to be used as an adjunct to the mainline of treatment against breast cancer.
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Antineoplásicos Fitogénicos/farmacología , Phoeniceae/química , Extractos Vegetales/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Regulación hacia Abajo/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Frutas/química , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
BACKGROUND: Mixed ligand-metal complexes are efficient chelating agents because of their flexible donor ability. Mixed ligand complexes containing hetero atoms sulphur, nitrogen and oxygen have been probed for their biological significance. METHODS: Nine mixed ligand-metal complexes of 2-(butan-2-ylidene) hydrazinecarbothioamide (2- butanone thiosemicarbazone) with pyridine, bipyridine and 2-picoline as co-ligands were synthesized with Cu, Co and Zn salts. The complexes were tested against MDA-MB231 (MDA) and A549 cell lines. Antibacterial activity was tested against Staphylococcus aureus and Escherichia coli. The drug character of the complexes was evaluated on parameters viz. physicochemical properties, bioactivity scores, toxicity assessment and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profile using various automated softwares. Molecular docking was performed against Ribonucleotide Reductase (RR) and topoisomerase II (topo II). RESULTS: The mixed ligand-metal complexes were synthesized by condensation reaction for 4-5 h. The characterization was done by elemental analysis, 1H-NMR, FT-IR, molar conductance and UV spectroscopic techniques. Molecular docking results showed that [Cu(C5H11N3S)(py)2(CH3COO)2], [Zn(C5H11N3S)(bpy)(SO4)] and [Zn(C5H11N3S)(2-pic)2(SO4)] displayed the lowest binding energies with respect to RR. Against topo II [Cu(C5H11N3S)(py)2(CH3COO)2], [Cu(C5H11N3S)(bpy)(CH3COO)2] and [Zn(C5H11N3S)(2-pic)2(SO4)] had the lowest energies. The druglikness assessment was done using Leadlikeness and Lipinski's rules. Not more than two violations were obtained in case of each filtering rule showing drug-like character of the mixed ligand complexes. Some of the complexes exhibited positive bioactivity scores and almost all the complexes were predicted to be safe with no hazardous effects as predicted by the toxicity assessment. Ames test predicted the non-mutagenic nature of the complexes. CONCLUSION: In vitro activity evaluation showed that [Zn(C5H11N3S)(py)2(SO4)], [Co(C5H11N3S(bpy) (Cl)2] and [Cu(C5H11N3S)(2-pic)2(CH3COO)2] were active against MDA. Against A549 [Co(C5H11N3S)(py)2(Cl)2], [Cu(C5H11N3S)(py)2(CH3COO)2] and [Co(C5H11N3S(bpy)(Cl)2] were active. Antibacterial evaluation showed that [Co(C5H11N3S)(bpy)(Cl)2], [Zn(C5H11N3S)(2-pic)2(SO4)] and [Cu(C5H11N3S)(2-pic)2(CH3COO)2] were active against S. aureus. Against E. coli, [Zn(C5H11N3S)(2- pic)2(SO4)] showed activity at 18-20 mg dose range.