In silico design and evaluation of a multiepitope vaccine targeting the nucleoprotein of Puumala orthohantavirus.

The Puumala orthohantavirus is present in the body of the bank vole (Myodes glareolus). Humans infected with this virus may develop hemorrhagic fever accompanying renal syndrome. In addition, the infection may further lead to the failure of an immune system completely. The present study aimed to propose a possible vaccine by employing bioinformatics techniques to identify B and T-cell antigens. The best multi-epitope of potential immunogenicity was generated by combining epitopes. Additionally, the linkers EAAAK, AAY, and GPGPG were utilized in order to link the epitopes successfully. Further, C-ImmSim was used to perform in silico immunological simulations upon the vaccine. For the purpose of conducting expression tests in Escherichia coli, the chimeric protein construct was cloned using Snapgene into the pET-9c vector. The designed vaccine showed adequate results, evidenced by the global population coverage and favorable immune response. The developed vaccine was found to be highly effective and to have excellent population coverage in a number of computer-based assessments. This work is fully dependent on the development of nucleoprotein-based vaccines, which would constitute a significant step forward if our findings were used in developing a global vaccination to combat the Puumala virus.

Netting into the Sophoretin pool: An approach to trace GSTP1 inhibitors for reversing chemoresistance.

Chemoresistance, a significant challenge in cancer treatment, is often associated with the cellular glutathione-related detoxification system. The GSTP1 isoenzyme (glutathione S-transferases) plays a critical role in the cytoplasmic inactivation of anticancer drugs. This suggests the identification of GSTP1 inhibitors to combat chemoresistance. We screened Sophoretin (also called quercetin) derivatives for molecular properties, pharmacokinetics, and toxicity profiles. Following that, we conducted molecular docking and simulations between selected derivatives and GSTP1. The best-docked complex, GSTP1-quercetin 7-O-ß-D-glucoside, exhibited a binding affinity of -8.1 kcal/mol, with no predicted toxicity and good pharmacokinetic properties. Molecular dynamics simulations confirmed the stability of this complex. Quercetin 7-O-ß-D-glucoside shows promise as a lead candidate for addressing chemoresistance in cancer patients, although further experimental studies are needed to validate its efficacy and therapeutic potential.

Computational pharmacology profiling of borapetoside C against melanoma.

Melanoma,also known as a 'black tumor', begins in the melanocytes when cells (that produce pigment) grows out of control. Immunological dysregulation, which raises the risk for multiple illnesses, including melanoma, may be influenced by stress tiggered through viral infection, long term effects of ultraviolet radiation, environmental pollutants etc. Borapetoside C is one of the phytoconstituents from Tinospora crispa, and its biological source has been reported for its antistress property. Network pharmacology and KEGG pathway analysis of borapetoside C-regulated proteins were conducted to identify the hub genes involved in melanoma development. Further, a molecular docking was performed between borapetoside C and targets involved in melanoma. Further, the top 3 complexes were selected based on the binding energy to conduct molecular dynamics simulations to evaluate the stability of ligand-protein complex followed by principal component analysis and dynamic cross-correlation matrix. In addition, borapetoside C was also screened for its pharmacokinetics and toxicity profile. Network Pharmacology studies and KEGG pathway analysis revealed 8 targets involved in melanoma. Molecular docking between borapetoside C and targets involved in melanoma identified 3 complexes with minimum binding i.e. borapetoside C- MAP2K1, MMP9, and EGFR. Further, molecular dynamics simulations showed a stable complex of borapetoside C with MMP9 and EGFR. The present study suggested that borapetoside C may target MMP9 and EGFR to possess an anti-melanoma property. This finding can be useful in developing a novel therapeutic agent against melanoma from a natural source.Communicated by Ramaswamy H. Sarma.

Integration of network pharmacology, molecular docking, and simulations to evaluate phytochemicals from Drymaria cordata against cervical cancer.

Introduction: Cervical cancer is prevalent among women worldwide. It is a type of cancer that occurs in the cells of the cervix, the lower part of the uterus. Mostly, it is observed in developing nations due to limited access to screening tools. Natural products with anticancer properties and fewer side effects have gained attention. Therefore, this study evaluates the potential of Drymaria cordata as a natural source for treating cervical cancer. Methodology: Phytocompounds present in Drymaria cordata were screened for their molecular properties and drug-likeness. The selected compounds were studied using systems biology tools such as network pharmacology, molecular docking, and molecular dynamics simulations, including MMGBSA studies. Results: Through network pharmacology, molecular docking, and molecular dynamics simulations, quercetin 3-O-ß-d-glucopyranosyl-(1→2)-rhamnopyranoside was identified as a hit compound targeting HRAS and VEGFA proteins. These proteins were found to be responsible for the maximum number of pathway modulations in cervical cancer. Conclusion: Drymaria cordata exhibits potential for treating cervical cancer due to the presence of quercetin 3-O-ß-d-glucopyranosyl-(1→2)-rhamnopyranoside. Further validation of these findings through in vitro and in vivo studies is required.

Natural Flavonoids as Potential Therapeutics in the Management of Diabetic Wound: A Review.

Flavonoids are important bioactive phenolic compounds abundant in plants and exhibit different therapeutic potentials. A wound is a significant problem in diabetic individuals. A hyperglycaemic environment alters the normal wound-healing process and increases the risk of microbial infection, leading to hospitalization, morbidity, and amputation. Flavonoids are an important class of phytochemicals with excellent antioxidant, anti-inflammatory, antimicrobial, antidiabetic, antitumor, and wound healing property. Quercetin, hesperidin, curcumin, kaempferol, apigenin, luteolin, morin, etc. have shown their wound healing potential. Flavonoids effectively exhibit antimicrobial activity, scavenge reactive oxygen species, augment endogenous antioxidants, reduce the expression and synthesis of inflammatory cytokines (i.e. IL-1ß, IL-6, TNF-α, NF-κB), inhibit inflammatory enzymes, enhance anti-inflammatory cytokine (IL-10), enhance insulin section, reduce insulin resistance, and control blood glucose level. Several flavonoids like hesperidin, curcumin, quercetin, rutin, naringin, and luteolin have shown their potential in managing diabetic wounds. Natural products that maintain glucose haemostatic, exert anti-inflammatory activity, suppress/inhibit microbial growth, modulate cytokines, inhibit matrix metalloproteinase (MMP), stimulate angiogenesis and extracellular matrix, and modulate growth factor can be considered as a potential therapeutic lead to treat diabetic wound. Flavonoids were found to play a positive role in management of diabetic wounds by regulating MMP-2, MMP-8, MMP-9, MMP-13, Ras/Raf/ MEK/ERK, PI3K/Akt, and nitric oxide pathways. Therefore, it can be assumed that flavonoids could be potential therapeutics to prevent devastating effects of diabetic wounds. This paper focused on the potential role of flavonoids in managing diabetic wounds and discussed their possible mechanism of action.

Targeting Melanoma with a phytochemical pool: Tailing Makisterone C.

BACKGROUND AND OBJECTIVE: According to World Health Organization, melanoma claims the lives of about 48000 people worldwide each year. The purpose of this study was to identify potential phytochemical pool from Diplazium esculentum against proteins that contribute to melanoma development. METHODS: The research was carried to locate potentially bioactive molecules and conduct a theoretical analysis of active ingredients from DE to impact melanoma. Network pharmacology, pharmacokinetics, protein network interaction, gene enrichment, survival, and infiltration analysis were conducted. Furthermore, molecular docking and molecular dynamics simulation was carried out for makisterone C-MAPK1, MAPK3, and AKT1 complexes. RESULTS: The potential phytochemical pool were identified (stigmast-5-en-3-ol, esculentic acid, rutin, and makisterone C) and based on network pharmacology and molecular docking studies, makisterone-C was proposed to be the most promising ingredient. Furthermore, the investigation revealed 14 genes as critical "hubs" involved in combating melanoma that are manipulated by the above-mentioned 4 active ingredients and modulate multiple signaling in melanoma development. CONCLUSION: This study insights into the potential anti-melanoma effects of phytochemical pool from Diplazium esculentum using network pharmacology analysis, molecular docking, and simulation tailing makisterone C as a lead moiety and suggests the need for makisterone C further evaluation in intervening melanoma progression.

In silico discovery of 3 novel quercetin derivatives against papain-like protease, spike protein, and 3C-like protease of SARS-CoV-2.

BACKGROUND: The derivatives of quercetin is known for their immune-modulating antiviral, anti-blood clotting, antioxidant, and also for its anti-inflammatory efficacy. The current study was therefore conducted to examine the noted novel derivatives of quercetin present in plant sources as an immune modulator and as an antiviral molecule in the COVID-19 disease and also to study their affinity of binding with potential three targets reported for coronavirus, i.e., papain-like protease, spike protein receptor-binding domain, and 3C-like protease. Based on the high-positive drug-likeness score, the reported derivatives of quercetin obtained from an open-source database were further filtered. Compounds with positive and high drug-likeness scores were further predicted for their potential targets using DIGEP-Pred software, and STRING was used to evaluate the interaction between modulated proteins. The associated pathways were recorded based on the Kyoto Encyclopedia of Genes and Genomes pathway database. Docking was performed finally using PyRx having AutoDock Vina to identify the efficacy of binding between quercetin derivatives with papain-like protease, spike protein receptor-binding domain, and 3C-like protease. The ligand that scored minimum binding energy was chosen to visualize the interaction between protein and ligand. Normal mode analysis in internal coordinates was done with normal mode analysis to evaluate the physical movement and stability of the best protein-ligand complexes using the iMODS server. RESULTS: Forty bioactive compounds with the highest positive drug-likeness scores were identified. These 40 bioactives were responsible for regulating different pathways associated with antiviral activity and modulation of immunity. Finally, three lead molecules were identified based on the molecular docking and dynamics simulation studies with the highest anti-COVID-19 and immunomodulatory potentials. Standard antiviral drug remdesivir on docking showed a binding affinity of - 5.8 kcal/mol with PLpro, - 6.4 kcal/mol with 3CLpro, and - 8.6 kcal/mol with spike protein receptor-binding domain of SARS-CoV-2, the discovered hit molecules quercetin 3-O-arabinoside 7-O-rhamnoside showed binding affinity of - 8.2 kcal/mol with PLpro, whereas quercetin 3-[rhamnosyl-(1- > 2)-alpha-L-arabinopyranoside] and quercetin-3-neohesperidoside-7-rhamnoside was predicted to have a binding affinity of - 8.5 kcal/mol and - 8.8 kcal/mol with spike protein receptor-binding domain and 3CLpro respectively CONCLUSION: Docking study revealed quercetin 3-O-arabinoside 7-O-rhamnoside to possess the highest binding affinity with papain-like protease, quercetin 3-[rhamnosyl-(1- > 2)-alpha-L-arabinopyranoside] with spike protein receptor-binding domain, and quercetin-3-neohesperidoside-7-rhamnoside with 3C-like protease and all the protein-ligand complexes were found to be stable after performing the normal mode analysis of the complexes in internal coordinates.

Evaluation of a novel melatonin-loaded gelatin sponge as a wound dressing.

BACKGROUND: For Melatonin, the pineal gland hormone, also known as the neuroendocrine hormone, influences angiogenesis by exerting a positive effect on fibroblast, monocyte, and cytokine proliferation. Formulation and study of characteristics of gelation-based Melatonin sponge crosslinked with fructose using the surfactant foaming and freeze-drying method for wound healing application was the objective of our study. The structure of the formulated gelatin sponge was observed using a scanning electron microscope and showed to have abundant and uniform pores. Characteristics were studied using digestibility test, water uptake test, porosity measurement test, moisture uptake test, tensile strength test, folding endurance test, scanning electron microscopy, Fourier transform infrared spectroscopy, and drug entrapment efficiency analysis. RESULTS: The obtained data showed that the formulated sponge had good mechanical properties, water uptake, and water retention capacities. In animal experiments, histological and macroscopic observations showed that wounds covered by gelatin loaded with a Melatonin sponge healed quickly. CONCLUSION: The formulated sponge was a potential wound healing material having suitable physical, mechanical properties and biocompatibility. The graphical abstract is shown in Figure 1.

Multi-Epitope Vaccine Design against Monkeypox Virus via Reverse Vaccinology Method Exploiting Immunoinformatic and Bioinformatic Approaches.

(1) Background: The monkeypox virus is a zoonotic orthopox DNA virus that is closely linked to the virus. In light of the growing concern about this virus, the current research set out to use bioinformatics and immunoinformatics to develop a potential vaccine against the virus. (2) Methods: A multiepitope vaccine was constructed from the B-cell and T-cell epitopes of the MPXVgp181 strain using adjuvant and different linkers. The constructed vaccine was predicted for antigenicity, allergenicity, toxicity, and population coverage. In silico immune simulation studies were also carried out. Expression analysis and cloning of the constructed vaccine was carried out in the pET-28a(+) vector using snapgene. (3) Results: The constructed vaccine was predicted to be antigenic, non-allergenic, and non-toxic. It was predicted to have excellent global population coverage and produced satisfactory immune response. The in silico expression and cloning studies were successful in E. coli, which makes the vaccine construct suitable for mass production in the pharmaceutical industry. (4) Conclusion: The constructed vaccine is based on the B-cell and T-cell epitopes obtained from the MPXVgp181 strain. This research can be useful in developing a vaccine to combat the monkeypox virus globally after performing in-depth in vitro and in vivo studies.