Integrated computational approach identifies potential inhibitors of ASK1-(JNK/P38) interaction signaling: new insights into cancer therapeutics.

Cancers are characterized by the aberrant expression of certain genes that trigger a cascade of molecular events that culminate in dysregulated cell division. Consequently, the inhibition of the products of these expressedgenes has emerged as a rational approach in cancer therapy. The apoptosis signal-regulating kinase 1 (ASK1) protein, encoded by the mitogen-activated protein kinase kinase kinase 5 (MAP3K5) gene, plays pertinent roles in the mediation of cell death induced by stress and inflammation, andis often found at elevated levels in cancer. Consequently, it has emerged as a molecular target for the development of potential chemotherapeutics through identification of selective inhibitors. However, there is still dearth of ASK1 inhibitors in clinical use. Hence, molecular modelling approaches were employed in this study to discover potential ASK1 inhibitors from phytochemicals. Twenty-five phytocompounds from four medicinal plants were tested for their inhibitory prowess via molecular docking. Interestingly, all the compounds exhibited promising inhibitory potentials for ASK1. However, further subjection to filtering procedures via different pipelines including drug-likeness evaluation, pharmacokinetics screening, toxicity profiling, and better affinities compared to the approved inhibitor resulted in three hit compounds namely ellagic acid, luteolin, and kaempferol with suitable properties. Profiling of the interactions formed between the hit\compounds and the targets revealed several interactions that were not present in that of the approved inhibitor, while molecular dynamics (MD) simulation revealed the complexes formed as stable. Conclusively, this study identified three compounds with ASK1 inhibitory potentials that are worthy of further exploration in in vitro and in vivo studies.Communicated by Ramaswamy H. Sarma.

Physiochemical analyses and molecular characterization of heavy metal-resistant bacteria from Ilesha gold mining sites in Nigeria.

BACKGROUND: The contribution of the processes involved and waste generated during gold mining to the increment of heavy metals concentration in the environment has been well established. While certain heavy metals are required for the normal functioning of an organism, certain heavy metals have been identified for their deleterious effects on the ecosystem and non-physiological roles in organisms. Hence, efforts aimed at reducing their concentration level are crucial. To this end, soil and water samples were collected from Ilesha gold mining, Osun State, Nigeria, and they were subjected to various analyses aimed at evaluating their various physicochemical parameters, heavy metal concentration, heavy metal-resistant bacteria isolation, and other analyses which culminated in the molecular characterization of heavy metal-resistant bacteria. RESULTS: Notably, the results obtained from this study revealed that the concentration of heavy metal in the water samples around the mining site was in the order Co > Zn > Cd > Pb > Hg while that of the soil samples was in the order Co > Cd > Pb > Hg > Zn. A minimum inhibitory concentration test performed on the bacteria isolates from the samples revealed some of the isolates could resist as high as 800 ppm of Co, Cd, and Zn, 400 ppm, and 100 ppm of Pb and Hg respectively. Molecular characterization of the isolates revealed them as Priestia aryabhattai and Enterobacter cloacae. CONCLUSION: Further analysis revealed the presence of heavy metal-resistant genes (HMRGs) including merA, cnrA, and pocC in the isolated Enterobacter cloacae. Ultimately, the bacteria identified in this study are good candidates for bioremediation and merit further investigation in efforts to bioremediate heavy metals in gold mining sites.

Network pharmacology and molecular docking-based identification of drug candidates and key targets of Allium sativum for colorectal cancer treatment.

Colorectal cancer (CRC) is a type of cancer with high morbidity and mortality in several developing and developed countries of the world. Its mortality and morbidity are predicted to increase over the next decade, hence, efforts aimed at combating it have remained unabated. In the context of its treatment, the use of chemotherapeutics is often limited by challenges including cost-ineffectiveness, side effects, and drug resistance. Hence, medicinal plants are actively being explored for alternatives. In this study, Allium sativum (A. sativum) was explored for the discovery of key compounds that are worthy of exploration in the context of CRC treatment and the potential mechanism of its anti-CRC effects. The bioactive compounds of A. sativum were retrieved and subjected to drug-likeness and pharmacokinetics properties evaluation, the putative targets of compounds with admirable properties were predicted using PharmMapper while the targets of CRC were retrieved from GeneCards. The interactions between the targets common to both were retrieved from the String database while Cytoscape software was used to visualize and analyze the interactions. Gene set enrichment analysis (GSEA) study revealed the biological processes and pathways A. sativum could potentially restore in CRC. These analyses revealed the key targets via which A. sativum compounds exert their anti-CRC properties, while molecular docking studies of the key compounds against the key targets revealed beta-sitosterol and alpha-bisabolene as the compounds with the highest binding affinity for the key targets. Ultimately, further experimental studies are needed to validate the findings of this study.Communicated by Ramaswamy H. Sarma.

Computer-aided analysis of quercetin mechanism of overcoming docetaxel resistance in docetaxel-resistant prostate cancer.

BACKGROUND: Prostate cancer (PC) is a silent but potent killer among men. In 2018, PC accounted for more than 350, 000 death cases while more than 1.2 million cases were diagnosed. Docetaxel, a chemotherapeutic drug belonging to the taxane family of drugs, is one of the most potent drugs in combating advanced PC. However, PC cells often evolve resistance against the regimen. Hence, necessitating the search for complementary and alternative therapies. Quercetin, a ubiquitous phytocompound with numerous pharmacological properties, has been reported to reverse docetaxel resistance (DR) in docetaxel-resistant prostate cancer (DRPC). Therefore, this study aimed to explore the mechanism via which quercetin reverses DR in DRPC using an integrative functional network and exploratory cancer genomic data analyses. RESULTS: The putative targets of quercetin were retrieved from relevant databases, while the differentially expressed genes (DEGs) in docetaxel-resistant prostate cancer (DRPC) were identified by analysing microarray data retrieved from the Gene Expression Omnibus (GEO) database. Subsequently, the protein-protein interaction (PPI) network of the overlapping genes between the DEGs and quercetin targets was retrieved from STRING, while the hub genes, which represent the key interacting genes of the network, were identified using the CytoHubba plug-in of Cytoscape. The hub genes were further subjected to a comprehensive analysis aimed at identifying their contribution to the immune microenvironment and overall survival (OS) of PC patients, while their alterations in PC patients were also revealed. The biological roles played by the hub genes in chemotherapeutic resistance include the positive regulation of developmental process, positive regulation of gene expression, negative regulation of cell death, and epithelial cell differentiation among others. CONCLUSION: Further analysis revealed epidermal growth factor receptor (EGFR) as the most pertinent target of quercetin in reversing DR in DRPC, while molecular docking simulation revealed an effective interaction between quercetin and EGFR. Ultimately, this study provides a scientific rationale for the further exploration of quercetin as a combinational therapy with docetaxel.

Identification of a 1, 8-naphthyridine-containing compound endowed with the inhibition of p53-MDM2/X interaction signaling: a computational perspective.

Various studies have established that molecules specific for MDMX inhibition or optimized for dual inhibition of p53-MDM2/MDMX interaction signaling are more suitable for activating the Tp53 gene in tumor cells. Nevertheless, there are sparse numbers of approved molecules to treat the health consequences brought by the lost p53 functions in tumor cells. Consequently, this study explored the potential of a small molecule ligand containing 1, 8-naphthyridine scaffold to act as a dual inhibitor of p53-MDM2/X interactions using computational methods. The results obtained from quantum mechanical calculations revealed our studied compound entitled CPO is more stable but less reactive compared to standard dual inhibitor RO2443. Like RO2443, CPO also exhibited good non-linear optical properties. The results of molecular docking studies predicted that CPO has a higher potential to inhibit MDM2/MDMX than RO2443. Furthermore, CPO was stable over 50 ns molecular dynamics (MD) simulation in complex with MDM2 and MDMX respectively. On the whole, CPO also exhibited good drug-likeness and pharmacokinetics properties compared to RO2443 and was found with more anti-cancer activity than RO2443 in bioactivity prediction. CPO is anticipated to elevate effectiveness and alleviate drug resistance in cancer therapy. Ultimately, our results provide an insight into the mechanism that underlay the inhibition of p53-MDM2/X interactions by a molecule containing 1, 8-naphthyridine scaffold in its molecular structure.

Unravelling the anti-inflammatory mechanism of Allium cepa: an integration of network pharmacology and molecular docking approaches.

Allium cepa, commonly known as onion, is a widely consumed spice that possesses numerous pharmacological properties. A. cepa bioactive components are often explored in the treatment of inflammation-related complications. However, the molecular mechanism via which they exert their anti-inflammatory effects remains unknown. Therefore, this study aimed to elucidate the anti-inflammatory mechanism of A. cepa bioactive components. Consequently, the bioactive compounds of A. cepa were obtained from a database, while the potential targets of the sixty-nine compounds with desirable pharmacokinetic properties were predicted. Subsequently, the targets of inflammation were acquired from the GeneCards database. The protein-protein interaction (PPI) between the sixty-six shared targets of the bioactive compounds and inflammation was retrieved from the String database and visualized using Cytoscape v3.9.1 software. Gene Ontology (GO) analysis of the ten core targets from the PPI network revealed that A. cepa bioactive compounds could be involved in regulating biological processes such as response to oxygen-containing compounds and response to inflammation while Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis revealed that A. cepa compounds might modulate pathways including AGE-RAGE signaling pathway, interleukin (IL)-17 signalling pathway, and tumor necrosis factor signaling pathway. Molecular docking analysis showed that 1-O-(4-Coumaroyl)-beta-D-glucose, stigmasterol, campesterol, and diosgenin have high binding affinities for core targets including EGFR, ALB, MMP9, CASP3, and CCL5. This study successfully elucidated the potential anti-inflammatory mechanism of A. cepa bioactive compounds, hence, providing new insights into the development of alternative anti-inflammatory drugs.

Immunoinformatics Studies and Design of a Potential Multi-Epitope Peptide Vaccine to Combat the Fatal Visceral Leishmaniasis.

Leishmaniasis is a neglected tropical disease caused by parasitic intracellular protozoa of the genus Leishmania. The visceral form of this disease caused by Leishmania donovani continues to constitute a major public health crisis, especially in countries of endemicity. In some cases, it is asymptomatic and comes with acute and chronic clinical outcomes such as weight loss, pancytopenia, hepatosplenomegaly, and death if left untreated. Over the years, the treatment of VL has relied solely on chemotherapeutic agents, but unfortunately, these drugs are now faced with challenges. Despite all efforts, no successful vaccine has been approved for VL. This could be as a result of limited knowledge/understanding of the immune mechanisms necessary to regulate parasite growth. Using a computational approach, this study explored the prospect of harnessing the properties of a disulfide isomerase protein of L. donovani amastigotses to develop a multi-epitope subunit vaccine candidate against the parasite. We designed a 248-amino acid multi-epitope vaccine with a predicted antigenicity probability of 0.897372. Analyses of immunogenicity, allergenicity, and multiple physiochemical parameters indicated that the constructed vaccine candidate was stable, non-allergenic, and immunogenic, making it compatible with humans and hence, a potentially viable and safe vaccine candidate against Leishmania spp. Parasites.

Designing a vaccine-based therapy against Epstein-Barr virus-associated tumors using immunoinformatics approach.

Epstein-Barr virus (EBV) is widely known due to its role in the etiology of infectious mononucleosis. However, it is the first oncovirus that was identified and has been implicated in the etiology of several types of cancers. Globally, EBV infection is associated with more than 200, 000 new cancer cases and 150, 000 deaths yearly. A prophylactic or therapeutic vaccine targeting tumors associated with EBV infection is currently lacking. Therefore, this study aimed to develop a multiepitope-based polyvalent vaccine against EBV-associated tumors using immunoinformatics approach. The latency-associated proteins (LAP) of three strains of the virus were used in this study. Potential epitopes predicted from the proteins were analyzed and selected based on several predicted properties. Thirty viable B-cell and T-cell epitopes were selected and conjugated using various linkers alongside beta-defensin 3 as an adjuvant and pan HLA DR-binding epitope (PADRE) sequence to improve the immunogenicity of the vaccine construct. Molecular docking studies of the vaccine construct against toll-like receptors (TLRs) showed it is capable of inducing immune response via recognition by TLRs while immune simulation studies showed it could induce both cellular and humoral immune responses. Furthermore, molecular dynamics study of the complex formed by the vaccine candidate and TLR-4 showed that the complex was stable. Ultimately, the designed vaccine showed desirable properties based on in silico evaluation; however, experimental studies are needed to validate the efficacy of the vaccine against EBV-associated tumors.