Search

The fourth most frequent type of cancer in women and the leading cause of mortality for females worldwide is cervical cancer. Traditionally, medicinal plants have been utilized to treat various illnesses and ailments. The molecular docking method is used in the current study to look into the phytoconstituents of Juglans regia's possible anticancer effects on cervical cancer target proteins. This work uses the microarray dataset analysis of GSE63678 from the NCBI Gene Expression Omnibus database to find differentially expressed genes. Furthermore, protein-protein interactions of differentially expressed genes were constructed using network biology techniques. The top five hub genes (IGF1, FGF2, ESR1, MYL9, and MYH11) are then determined by computing topological parameters with Cytohubba. In addition, molecular docking research was performed on Juglans regia phytocompounds that were extracted from the IMPPAT database versus hub genes that had been identified. Utilizing molecular dynamics, simulation confirmed that prioritized docked complexes with low binding energies were stable. [ABSTRACT FROM AUTHOR]

Schizophrenia is a mental illness affecting the normal lifestyle of adults and early adolescents incurring major symptoms as jumbled speech, involvement in everyday activities eventually got reduced, patients always struggle with attention and memory, reason being both the genetic and environmental factors responsible for altered brain chemistry and structure, resulting in schizophrenia and associated orphan diseases. The network biology describes the interactions among genes/proteins encoding molecular mechanisms of biological processes, development, and diseases. Besides, all the molecular networks, protein‐protein Interaction Networks have been significant in distinguishing the pathogenesis of diseases and thereby drug discovery. The present meta‐analysis prioritizes novel disease indications viz. rare and orphan diseases associated with target Glutamate Ionotropic Receptor NMDA Type Subunit 1, GRIN1 using text mining knowledge‐based tools. Furthermore, ZINC database was virtually screened, and binding conformation of selected compounds was performed and resulted in the identification of Narciclasine (ZINC04097652) and Alvespimycin (ZINC73138787) as potential inhibitors. Furthermore, docked complexes were subjected to MD simulation studies which suggests that the identified leads could be a better potential drug to recuperate schizophrenia. [ABSTRACT FROM AUTHOR]

Curcumin is a hydrophobic polyphenol derived from turmeric with potent anti-oxidant, anti-microbial, anti-inflammatory and anti-carcinogenic effects. Curcumin is degraded into various derivatives under in vitro and in vivo conditions, and it appears that its degradation may be responsible for the pharmacological effects of curcumin. The primary risk factor for the cause of gastric cancer is Helicobacter pylori (H. pylori). A virulence factor vacuolating cytotoxic A (VacA) is secreted by H. pylori as a 88 kDa monomer (p88), which can be fragmented into a 33 kDa N-terminal domain (p33) and a 55 kDa C-terminal domain (p55). Recently it has been reported that curcumin oxidation is required to inhibit the activity of another major H.pylori toxin CagA. We performed molecular docking of curcumin and its oxidative derivatives with p33 and p55 domains of VacA. Further, we have examined the effect of the oxidation of curcumin on the vacuolation activity of VacA protein. We observed the binding of curcumin to the p55 domain of VacA at five different sites with moderate binding affinities. Curcumin did not bind to p33 domain of VacA. Remarkably, cyclobutyl cyclopentadione and dihydroxy cyclopentadione, which are oxidized products of curcumin, showed a higher binding affinity with VacA protein at all sites except one as compared to parent curcumin itself. However, cyclobutyl cyclopentadione showed a significant binding affinity for the active site 5 of the p55 protein. Active site five (312–422) of p55 domain of VacA plays a crucial role in VacA-mediated vacuole formation. Invitro experiments showed that curcumin inhibited the vacuolation activity of H. pylori in human gastric cell line AGS cells whereas acetyl and diacetyl curcumin, which cannot be oxidized, failed to inhibit the vacuolation in AGS cells after H. pylori infection. Here our data showed that oxidation is essential for the activity of curcumin in inhibiting the vacuolation activity of H. pylori. Synthesis of these oxidized curcumin derivatives could potentially provide new therapeutic drug molecules for inhibiting H. pylori-mediated pathogenesis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recurrent outbreaks of respiratory viruses like SARS-CoV (severe acute respiratory syndrome-coronavirus, 2002), MERS (Middle East respiratory syndrome, 2012) including the ongoing SARS-CoV-2 (2019) pandemic warrants for a single-broad-spectrum vaccine against these respiratory viruses. METHODS: In the present study, phylogenetic analysis followed by in-silico identification of vaccine candidates for SARS, MERS and SARS- CoV-2 was performed by exploiting T-cell and B-cell mapping to ascertain the best possible epitopes for effector humoral- and cell-mediated immune response. Further, population-coverage analysis of the identified epitopes followed by the designing of chimera of epitope-based vaccine was done using linkers and adjuvants. Docking study was done to appraise the interaction of the proposed vaccine with ACE2 (angiotensin converting enzyme-2) receptor (SARS and SARS-CoV-2) and HLA-B7 (human leukocyte antigen) receptor (MERS). The stability of the vaccine chimera was confirmed by molecular dynamics performed for 20 ns; this was followed by codon optimization and in-silico cloning. RESULTS: Phylogenetic analysis revealed similarity among SARS-CoV-2, SARS-CoV and bat SARS-like coronavirus. Both, SARS-CoV and SARS-CoV-2 were from different class than MERS, whereas SARS-CoV-2 showed more relatedness with Bat SARS-like coronaviruses. The most suitable epitopes found were LSFELLNAPATVCGP (SARS), LVTLAILTALRLCAY (SARS-CoV-2) and YTSAFNWLL (MERS) with nearly 98% population coverage. Molecular docking followed by simulation studies revealed high number of hydrogen bonds, stable RMSD values and acceptable RMSF flexibility scores, indicating stable interactions of the vaccine with ACE2 and MHC receptors (Major histocompat-ibility complex). Expression of the designed multiepitope vaccine in E. coli (Escherichia coli) expression system was confirmed by in-silico cloning/codon optimization. CONCLUSIONS: Further, in-vitro and in-vivo experimental validation studies are required to endorse our current findings. [ABSTRACT FROM AUTHOR]

BACKGROUND: To combat the global health issue caused by SARS-CoV2, scientists are attempting various therapeutic approaches towards drug discovery including computational biology and drug-repurposing. Recent studies have highlighted the conserved nature of RNA-dependent RNA polymerase (RdRp) of coronaviruses affecting human, bat and animals. In this study attempts have been made to identify the potential inhibitors of RdRp by utilizing molecular docking and MD simulation studies. METHODS: Systematic structure-based screening of chemical compounds from public libraries was performed to identify the potential lead molecules inhibiting RdRp. This structure driven clustering of compounds is based on decision tree model generated by combining two properties: 1) shape descriptors; and 2) critical number of multiple bonds. The enabled screening of potential chemical compounds was subjected to molecular docking followed by molecular dynamics simulation studies. RESULTS: The results revealed that the stability of protein-drug complex structure was in the order of RdRp-Oxoglaucine >RdRp-Flutroline >RdRp-Brucine complex. CONCLUSIONS: This study identifies Oxoglaucine, Brucine and Flutroline as prospective inhibiting agents of SARS-CoV-2 RdRp and further warrants for experimental validation. ( [ABSTRACT FROM AUTHOR]

Network medicine provides network theoretical tools, methods and properties to study underlying laws governing human interactome to identify disease states and disease complexity leading to drug discovery. Within this framework, we investigated the topological properties of ovarian cancer network (OCN) and the roles of hubs to understand OCN organization to address disease states and complexity. The OCN constructed from the experimentally verified genes exhibits fractal nature in the topological properties with deeply rooted functional communities indicating self-organizing behavior. The network properties at all levels of organization obey one parameter scaling law which lacks centrality lethality rule. We showed that |$\langle k\rangle $| can be taken as a scaling parameter, where, power law exponent can be estimated from the ratio of network diameters. The betweenness centrality |$C_B$| shows two distinct behaviors one shown by high degree hubs and the other by segregated low degree nodes. The |$C_B$| power law exponent is found to connect the exponents of distributions of high and low degree nodes. OCN showed the absence of rich-club formation which leads to the missing of a number of attractors in the network causing formation of weakly tied diverse functional modules to keep optimal network efficiency. In OCN, provincial and connector hubs, which includes identified key regulators, take major responsibility to keep the OCN integrity and organization. Further, most of the key regulators are found to be over expressed and positively correlated with immune infiltrates. Finally, few potential drugs are identified related to the key regulators. [ABSTRACT FROM AUTHOR]

To date, several Glucosyltransferase C (GtfC) inhibitors have been identified and experimentally validated. All these inhibitors have been validated at different experimental conditions like degree of purity, animal models, kinetic conditions, experimental environment etc.; and most of these inhibitors (ligands) proved to be quite effective in their respective validation environment. However, due to varied experimental validation conditions, and absence of molecular interaction data, there is no way to prioritize these validated ligands for their inhibition potential against GtfC. The present study is a novel attempt of comparative evaluation of the interaction of the validated ligands on a single platform and under similar conditions with a dual objective, i.e. ligand prioritization for their respective inhibitory potential and elucidation of the involved unknown molecular interactions. Carbohydrate derivatives (6-Deoxy sucrose and Trichloro-galactosucrose) were identified as the most promising GtfC inhibitors. In addition, Asp588, Trp517, and Asn481 amino acid residues of the domain A1 proved vital for the inhibitory effect. The study highlights the importance of the comparative analysis of the validated ligands in order to identify the most promising leads for drug discovery against dental caries. [ABSTRACT FROM AUTHOR]