The artificial neural network selects saccharides from natural sources a promise for potential FimH inhibitor to prevent UTI infections.

The major challenge in the development of affordable medicines from natural sources is the unavailability of logical protocols to explain their mechanism of action in biological targets. FimH (Type 1 fimbrin with D-mannose specific adhesion property), a lectin on E. coli cell surface is a promising target to combat the urinary tract infection (UTI). The present study aimed at predicting the inhibitory capacity of saccharides on FimH. As mannosides are considered FimH inhibitors, the readily accessible saccharides from the PubChem collection were utilized. The artificial neural networks (ANN)-based machine learning algorithm Self-organizing map (SOM) has been successfully employed in predicting active molecules as they could discover relationships through self-organization for the ligand-based virtual screening. Docking was used for the structure-based virtual screening and molecular dynamic simulation for validation. The result revealed that the predicted molecules malonyl hexose and mannosyl glucosyl glycerate exhibit exactly similar binding interactions and better docking scores as that of the reference bioassay active, heptyl mannose. The pharmacokinetic profile matches that of the selected bioflavonoids (quercetin malonyl hexose, kaempferol malonyl hexose) and has better values than the control drug bioflavonoid, monoxerutin. Thus, these two molecules can effectively inhibit type 1 fimbrial adhesin, as antibiotics against E. coli and can be explored as a prophylactic against UTIs. Moreover, this investigation can pave the way to the exploration of the potential benefits of plant-based treatments. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00212-5.

Current Drugs and their Therapeutic Targets for Hypoxia-inducible Factors in Cancer.

Hypoxia, a prevalent characteristic of both solid and liquid malignancies, is found to regulate how genes are expressed in a way that promotes cellular adaptability and survival. Metastasis is controlled by hypoxia-inducible factors (HIFs). HIFs are dimeric protein molecules made up of an oxygen (O2) responsive HIF-1α, HIF-2α, or HIF-3α domain and a periodically produced HIF-1ß portion (also known as ARNT). Nevertheless, it is important to note that HIFs degrade under normoxic conditions. A large multitude of different biological operations, including vessels generation, oxygen delivery, stemness, pluripotency, multiplication, epithelial to mesenchymal shift, metastatic prevalence and intrusion, redox equilibrium, and programmed cell death, are strictly controlled by over 70 immediate HIF target genes that have been reported. Metabolic reprogramming, which modulates cellular energy generation aside from oxidative phosphorylation and concerning glycolysis, is among the core tasks of HIF target genes. As a result, choosing HIFs as a primary target in the treatment of various tumors is essential. We have a very limited understanding of this extremely complex topic, which is characterised by hypoxia- induced resistance. In order to combat this, scientists are investigating numerous cutting-edge approaches. Traditional chemotherapeutic drugs used to treat cancer are frequently linked to unfavourable side effects and the development of chemoresistance. The use of natural compounds in conjunction with chemotherapy drugs is rising as a result of their capacity to alter a number of molecular practices with a lower detrimental impact. Experimental and clinical research is accumulating evidence that phytochemicals can influence the genesis and progression of cancer by favourably modulating a number of signalling pathways. Combinations of phytochemicals are potent cancer treatment options because they incentivise apoptosis, limit cell prevalence, make cancerous cells more susceptible, and escalate immunity. Despite being characterised, HIF-1-independent mechanisms for medication resistance in hypoxia are still infrequently reported. The prime aim of the article is to summarise the most recent research on the molecular basis of hypoxia-induced chemoresistance and how chemotherapy and phytochemicals can be used to treat cancer patients who are resistant to drugs.

Molecular docking analysis reveals the functional inhibitory effect of Genistein and Quercetin on TMPRSS2: SARS-COV-2 cell entry facilitator spike protein.

BACKGROUND: The Transmembrane Serine Protease 2 (TMPRSS2) of human cell plays a significant role in proteolytic cleavage of SARS-Cov-2 coronavirus spike protein and subsequent priming to the receptor ACE2. Approaching TMPRSS2 as a therapeutic target for the inhibition of SARS-Cov-2 infection is highly promising. Hence, in the present study, we docked the binding efficacy of ten naturally available phyto compounds with known anti-viral potential with TMPRSS2. The aim is to identify the best phyto compound with a high functional affinity towards the active site of the TMPRSS2 with the aid of two different docking software. Molecular Dynamic Simulations were performed to analyse the conformational space of the binding pocket of the target protein with selected molecules. RESULTS: Docking analysis using PyRx version 0.8 along with AutoDockVina reveals that among the screened phyto compounds, Genistein shows the maximum binding affinity towards the hydrophobic substrate-binding site of TMPRSS2 with three hydrogen bonds interaction ( - 7.5 kcal/mol). On the other hand, molecular docking analysis using Schrodinger identified Quercetin as the most potent phyto compound with a maximum binding affinity towards the hydrophilic catalytic site of TMPRSS2 ( - 7.847 kcal/mol) with three hydrogen bonds interaction. The molecular dynamics simulation reveals that the Quercetin-TMPRSS complex is stable until 50 ns and forms stable interaction with the protein ( - 22.37 kcal/mol of MM-PBSA binding free energy). Genistein creates a weak interaction with the loop residues and hence has an unstable binding and exits from the binding pocket. CONCLUSION: The compounds, Quercetin and Genistein, can inhibit the TMPRSS2 guided priming of the spike protein. The compounds could reduce the interaction of the host cell with the type I transmembrane glycoprotein to prevent the entry of the virus. The critical finding is that compared to Genistein, Quercetin exhibits higher binding affinity with the catalytic unit of TMPRSS2 and forms a stable complex with the target. Thus, enhancing our innate immunity by consuming foods rich in Quercetin and Genistein or developing a novel drug in the combination of Quercetin and Genistein could be the brilliant choices to prevent SARS-Cov-2 infection when we consider the present chaos associated with vaccines and anti-viral medicines.

Artificial Neural Network-Based Study Predicts GS-441524 as a Potential Inhibitor of SARS-CoV-2 Activator Protein Furin: a Polypharmacology Approach.

Furin, a pro-protein convertase, plays a significant role as a biological scissor in bacterial, viral, and even mammalian substrates which in turn decides the fate of many viral and bacterial infections along with the numerous ailments caused by cancer, diabetes, inflammations, and neurological disorders. In the wake of the current pandemic caused by the virus SARS-CoV-2, furin has become the center of attraction for researchers as the spike protein contains a polybasic furin cleavage site. In the present work, we have searched for novel inhibitors against this interesting human target from FDA-approved antiviral. To enhance the selection of new inhibitors, we employed Kohonen's artificial neural network-based self-organizing maps for ligand-based virtual screening. Promising results were obtained which can help in drug repurposing and network pharmacology studies can address the errors generated due to promiscuity/polypharmacology. We found 15 existing FDA antiviral drugs having the potential to inhibit furin. Among these, six compounds have targets on important human proteins (LDLR, FCGR1A, PCK1, TLR7, DNA, and PNP). The role of these 15 drugs inhibiting furin can be established by studying further on patients infected with number of viruses including SARS-CoV-2. Here we propose two promising candidate FDA drugs GS-441524 and Grazoprevir (MK-5172) for repurposing as inhibitors of furin. The best results were observed with GS-441524.

Unravelling Vitamin B12 as a potential inhibitor against SARS-CoV-2: A computational approach.

The new severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) is the etiological agent of Coronavirus disease 2019 (COVID-19), which becomes an eventual pandemic outbreak. Lack of proper therapeutic management has accelerated the researchers to repurpose existing drugs with known preclinical and toxicity profiles, which can easily enter Phase 3 or 4 or can be used directly in clinical settings. Vitamins are necessary nutrients for cell growth, function, and development. Furthermore, they play an important role in pathogen defence via cell-mediated responses and boost immunity. Using a computational approach, we intend to identify the probable inhibitory effect of all vitamins on the drug targets of COVID-19. The computational analysis demonstrated that vitamin B12 resulted in depicting suitable significant binding with furin, RNA dependent RNA polymerase (RdRp), Main proteases (Mpro), ORF3a and ORF7a and Vitamin D3 with spike protein and vitamin B9 with non structural protein 3 (NSP3). A detailed examination of vitamins suggests that vitamin B12 may be the component that reduces virulence by blocking furin which is responsible for entry of virus in the host cell. Details from the Molecular Dynamics (MD) simulation study aided in determining vitamin B12 as a possible furin inhibitor.

Molecular Landscape and Computational Screening of the Natural inhibitors against HPV16 E6 Oncoprotein.

BACKGROUND: Human Papillomavirus (HPV) is a small, non-enveloped, icosahedral and double-stranded DNA virus with a genome of 8 kb, belonging to the papillomaviridae family. HPV has been associated with 99.7% cases of cervical squamous cell carcinoma worldwide. The HPV E6 protein is known as a potent oncogene and is closely allied with the events that result in the malignant transformation of virally infected cells. OBJECTIVE: The present study aims to target plant derived anticancer molecules for HPV driven cancer using a computational approach. METHODS: In this study, E6 oncoprotein was targeted by 101 plant-derived nutraceuticals using the molecular docking method. The multiple sequence analysis and phylogenetic analysis of low risk and high risk 28 HPV E6 proteins were performed. RESULTS: Withanolide D, Ginkgetin, Theaflavin, Hesperidin, and Quercetin-3-gluconide were identified as the potential inhibitors of HPV 16 E6 protein. The zinc finger domain was identified on all variants of HPV E6 oncoprotein while high-risk HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV58, HPV68 and HPV73: probable risk HPV53 and low-risk HPV43 and HPV70 contain PDZ domain. CONCLUSION: The current study using bioinformatics analysis approaches reveals a promising platform for developing anti-cancerous competitive inhibitors targeting HPV.
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Significant Role of Segmental Duplications and SIDD Sites in Chromosomal Translocations of Hematological Malignancies: A Multi-parametric Bioinformatic Analysis.

Recurrent non-random chromosomal translocations are hallmark characteristics of leukemogenesis, and however, molecular mechanisms underlying these rearrangements are less explored. The fundamental question is, why and how chromosomes break and reunite so precisely in the genome. Meticulous understanding of mechanism leading to chromosomal rearrangement can be achieved by characterizing breakpoints. To address this hypothesis, a novel multi-parametric computational approach for characterization of major leukemic translocations within and around breakpoint region was performed. To best of our knowledge, this bioinformatic analysis is unique in finding the presence of segmental duplications (SDs) flanking breakpoints of all major leukemic translocation. Breakpoint islands (BpIs) were analyzed for stress-induced duplex destabilization (SIDD) sites along with other complex genomic architecture and physicochemical properties. Our study distinctly emphasizes on the probable correlative role of SDs, SIDD sites and various genomic features in the occurrence of breakpoints. Further, it also highlights potential features which may be playing a crucial role in causing double-strand breaks, leading to translocation.