Phytochemicals Neogitogenin and Samogenin Hold Potentials for Hepatocyte Growth Factor Receptor-Targeted Cancer Treatment.

Protein kinases are key targets for cancer therapies, with the c-Met receptor tyrosine kinase (MET) and its ligand, hepatocyte growth factor, playing a role in various cancers, including non-small cell lung cancer, gastric cancer, and hepatocellular carcinoma. Although small-molecule inhibitors have been designed to target MET, the development of drug resistance remains a significant challenge to advancing therapeutic strategies. In this study, we employed virtual screening of plant-based compounds sourced from the IMPPAT 2.0 databank to identify potent inhibitors of MET. Preliminary filtering based on the physicochemical parameters following Lipinski's rule of five and pan-assay interference compounds criteria were applied to prioritize hits. Subsequent molecular docking, pharmacokinetic evaluation, prediction of activity spectra for biologically active substances, and specificity assessments facilitated the identification of two promising phytochemicals, neogitogenin and samogenin. Both phytochemicals exhibited considerable drug-like properties with notable binding affinity and selectivity toward MET. Molecular dynamics simulation studies showed the conformational stability of MET with neogitogenin and samogenin. Taken together, these findings suggest that neogitogenin and samogenin hold potential as lead molecules for the development of MET-targeted therapeutics. We call for further evaluations of these phytochemicals in preclinical and experimental studies for anticancer drug discovery and development.

Targeting prostate cancer via therapeutic targeting of PIM-1 kinase by Naringenin and Quercetin.

PIM-1 kinase belongs to the Ser/Thr kinases family, an attractive therapeutic target for prostate cancer. Here, we screened about 100 natural substances to find potential PIM-1 inhibitors. Two natural compounds, Naringenin and Quercetin, were finally selected based on their PIM-1 inhibitory potential and binding affinities. The docking score of Naringenin and Quercetin with PIM-1 is -8.4 and - 8.1 kcal/mol, respectively. Fluorescence binding studies revealed a strong affinity (Ka values, 3.1 × 104 M-1 and 4.6 × 107 M-1 for Naringenin and Quercetin, respectively) with excellent IC50 values for Naringenin and Quercetin (28.6 µM and 34.9 µM, respectively). Both compounds inhibited the growth of prostate cancer cells (LNCaP) in a dose-dependent manner, with the IC50 value of Naringenin at 17.5 µM and Quercetin at 8.88 µM. To obtain deeper insights into the PIM-1 inhibitory effect of Naringenin and Quercetin, we performed extensive molecular dynamics simulation studies, which provided insights into the binding mechanisms of PIM-1 inhibitors. Finally, Naringenin and Quercetin were suggested to serve as potent PIM-1 inhibitors, offering targeted treatments of prostate cancer. In addition, our findings may help to design novel Naringenin and Quercetin derivatives that could be effective in therapeutic targeting of prostate cancer.

Exploring molecular mechanisms, therapeutic strategies, and clinical manifestations of Huntington's disease.

Huntington's disease (HD) is a paradigm of a genetic neurodegenerative disorder characterized by the expansion of CAG repeats in the HTT gene. This extensive review investigates the molecular complexities of HD by highlighting the pathogenic mechanisms initiated by the mutant huntingtin protein. Adverse outcomes of HD include mitochondrial dysfunction, compromised protein clearance, and disruption of intracellular signaling, consequently contributing to the gradual deterioration of neurons. Numerous therapeutic strategies, particularly precision medicine, are currently used for HD management. Antisense oligonucleotides, such as Tominersen, play a leading role in targeting and modulating the expression of mutant huntingtin. Despite the promise of these therapies, challenges persist, particularly in improving delivery systems and the necessity for long-term safety assessments. Considering the future landscape, the review delineates promising directions for HD research and treatment. Innovations such as Clustered regularly interspaced short palindromic repeats associated system therapies (CRISPR)-based genome editing and emerging neuroprotective approaches present unprecedented opportunities for intervention. Collaborative interdisciplinary endeavors and a more insightful understanding of HD pathogenesis are on the verge of reshaping the therapeutic landscape. As we navigate the intricate landscape of HD, this review serves as a guide for unraveling the intricacies of this disease and progressing toward transformative treatments.

Elucidating the Impact of Deleterious Mutations on IGHG1 and Their Association with Huntington's Disease.

Huntington's disease (HD) is a chronic, inherited neurodegenerative condition marked by chorea, dementia, and changes in personality. The primary cause of HD is a mutation characterized by the expansion of a triplet repeat (CAG) within the huntingtin gene located on chromosome 4. Despite substantial progress in elucidating the molecular and cellular mechanisms of HD, an effective treatment for this disorder is not available so far. In recent years, researchers have been interested in studying cerebrospinal fluid (CSF) as a source of biomarkers that could aid in the diagnosis and therapeutic development of this disorder. Immunoglobulin heavy constant gamma 1 (IGHG1) is one of the CSF proteins found to increase significantly in HD. Considering this, it is reasonable to study the potential involvement of deleterious mutations in IGHG1 in the pathogenesis of this disorder. In this study, we explored the potential impact of deleterious mutations on IGHG1 and their subsequent association with HD. We evaluated 126 single-point amino acid substitutions for their impact on the structure and functionality of the IGHG1 protein while exploiting multiple computational resources such as SIFT, PolyPhen-2, FATHMM, SNPs&Go mCSM, DynaMut2, MAESTROweb, PremPS, MutPred2, and PhD-SNP. The sequence- and structure-based tools highlighted 10 amino acid substitutions that were deleterious and destabilizing. Subsequently, out of these 10 mutations, eight variants (Y32C, Y32D, P34S, V39E, C83R, C83Y, V85M, and H87Q) were identified as pathogenic by disease phenotype predictors. Finally, two pathogenic variants (Y32C and P34S) were found to reduce the solubility of the protein, suggesting their propensity to form protein aggregates. These variants also exhibited higher residual frustration within the protein structure. Considering these findings, the study hypothesized that the identified variants of IGHG1 may compromise its function and potentially contribute to HD pathogenesis.

Boron Facilitates Amelioration of Hepatic Injury by the Osmolyte Glycine and Resolves Injury by Improving the Tissue Redox Homeostasis.

Background: Glycine is a conditional non-essential amino acid in human and other mammals. It is abundant in the liver and is known for a wide spectrum of characteristics including the antioxidant, antiinflammatory, immunomodulatory, and cryoprotective effects. The amino acid is a naturally occurring osmolyte compatible with protein surface interactions and has been reported in literature as a potent therapeutic immuno-nutrient for liver diseases such as alcoholic liver disease. Oral glycine administration protects ethanol-induced liver injury, improves serum and tissue lipid profile, and alleviates hepatic injury in various conditions. In recent years, sodium salt of boron (borax) has been reported for its beneficial effects on cellular stress, including the effects on cell survival, immunity, and tissue redox state. Incidentally both glycine and boron prevent apoptosis and promote cell survival under stress. Objective: This study investigates the beneficial effect of borax on liver protection by glycine. Methods: Briefly, liver toxicity was induced in rats by a single intraperitoneal injection of thioacetamide (400 mg/kg b. wt.). Results: Significant changes in oxidative stress and liver function test parameters, the molybdenum Fe-S flavin hydroxylase activity, nitric oxide and tissue histopathology were observed in thioacetamide treated positive control group. The changes were ameliorated both by glycine as well as borax, but the combinatorial treatment yielded a better response indicating the impact of boron supplementation on glycine mediated protection of liver injury in experimental animal model. Conclusions: The study has clinical implications as the hepatotoxicity caused by thioacetamide mimics features of hepatitis C infection in human.

Identification of potential inhibitors of tropomyosin receptor kinase B targeting CNS-related disorders and cancers.

Tropomyosin receptor kinase B (TrkB), also known as neurotrophic tyrosine kinase receptor type 2 (NTRK2), is a protein that belongs to the family of receptor tyrosine kinases (RTKs). NTRK2 plays a crucial role in regulating the development and maturation of the central nervous system (CNS) and peripheral nervous system (PNS). Elevated TrkB expression levels observed in different pathological conditions make it a potential target for therapeutic interventions against neurological disorders, including depression, anxiety, Alzheimer's disease, Parkinson's disease, and certain types of cancer. Targeting TrkB using small molecule inhibitors is a promising strategy for the treatment of a variety of neurological disorders. In this research, a systematic virtual screening was carried out on phytoconstituents found in the IMPPAT library to identify compounds potentially inhibiting TrkB. The retrieved compounds from the IMPPAT library were first filtered using Lipinski's rule of five. The compounds were then sorted based on their docking score and ligand efficiency. In addition, PAINS, ADMET, and PASS evaluations were carried out for selecting drug-like compounds. Finally, in interaction analysis, we found two phytoconstituents, Wedelolactone and 3,8-dihydroxy-1-methylanthraquinone-2-carboxylic acid (DMCA), which possessed considerable docking scores and specificity on the TrkB ATP-binding pocket. The selected compounds were further assessed employing molecular dynamics (MD) simulations and essential dynamics. The results revealed that the elucidated compounds bind well with the TrkB binding pocket and lead to fewer conformations fluctuations. This study highlighted using phytoconstituents, Wedelolactone and DMCA as starting leads in developing novel TrkB inhibitors.Communicated by Ramaswamy H. Sarma.

Identification of natural product-based effective inhibitors of spleen tyrosine kinase (SYK) through virtual screening and molecular dynamics simulation approaches.

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase that plays an essential role in signal transduction across different cell types. In the context of allergy and autoimmune disorders, it is a crucial regulator of immune receptor signaling in inflammatory cells such as B cells, mast cells, macrophages, and neutrophils. Developing SYK kinase inhibitors has gained significant interest for potential therapeutic applications in neurological and cancer-related conditions. The clinical use of the most advanced SYK inhibitor, Fostamatinib, has been limited due to its unwanted side effects. Thus, a more targeted approach to SYK inhibition would provide a more comprehensive treatment window. In this study, we used a virtual screening approach to identify potential SYK inhibitors from natural compounds from the IMPPAT database. We identified two compounds, Isolysergic acid and Michelanugine, which showed strong affinity and specificity for the SYK binding pocket. All-atom molecular dynamics (MD) simulations were also performed to explore the stability, conformational changes, and interaction mechanism of SYK in complexes with the identified compounds. The identified compounds might have the potential to be developed into promising SYK inhibitors for the treatment of various diseases, including autoimmune disorders, cancer, and inflammatory diseases. This work aims to identify potential phytochemicals to develop a new protein kinase inhibitor for treating advanced malignancies by providing an updated understanding of the role of SYK.Communicated by Ramaswamy H. Sarma.

Targeting Cathepsin L in Cancer Management: Leveraging Machine Learning, Structure-Based Virtual Screening, and Molecular Dynamics Studies.

Cathepsin L (CTSL) expression is dysregulated in a variety of cancers. Extensive empirical evidence indicates their direct participation in cancer growth, angiogenic processes, metastatic dissemination, and the development of treatment resistance. Currently, no natural CTSL inhibitors are approved for clinical use. Consequently, the development of novel CTSL inhibition strategies is an urgent necessity. In this study, a combined machine learning (ML) and structure-based virtual screening strategy was employed to identify potential natural CTSL inhibitors. The random forest ML model was trained on IC50 values. The accuracy of the trained model was over 90%. Furthermore, we used this ML model to screen the Biopurify and Targetmol natural compound libraries, yielding 149 hits with prediction scores >0.6. These hits were subsequently selected for virtual screening using a structure-based approach, yielding 13 hits with higher binding affinity compared to the positive control (AZ12878478). Two of these hits, ZINC4097985 and ZINC4098355, have been shown to strongly bind CTSL proteins. In addition to drug-like properties, both compounds demonstrated high affinity, ligand efficiency, and specificity for the CTSL binding pocket. Furthermore, in molecular dynamics simulations spanning 200 ns, these compounds formed stable protein-ligand complexes. ZINC4097985 and ZINC4098355 can be considered promising candidates for CTSL inhibition after experimental validation, with the potential to provide therapeutic benefits in cancer management.

Deciphering the binding mechanism of an anti-cancer phytochemical plumbagin with calf thymus DNA using biophysical and in silico techniques.

Plumbagin (PLM), a plant derivative, is well known for a wide range of therapeutic effects in humans including anti-cancer, anti-inflammatory, anti-oxidant, and anti-microbial. Cytotoxic and genotoxic potential of this phytochemical has been studied which demands further insight. DNA being a major target for several drugs was taken to study against PLM to understand its effects on the cellular system. UV-Vis spectroscopy has indicated the binding of PLM to ctDNA and dye displacement assays have confirmed the formation of PLM-ctDNA complex. The insignificant changes in circular dichroism spectra suggested that PLM is not affecting the structural makeup of the ctDNA, hence the binding could be peripheral and not intercalating. Further, the relative viscosity and minimal change in melting temperature upon the complex formation supported this finding and confirmed the groove binding of PLM. Molecular docking analysis and simulation studies also show PLM as a minor groove binder to DNA and provide details on the interaction dynamics of PLM-DNA complex. Docking followed by a 100 ns simulation reveals the negative Gibbs free energy change (∆G = -6.6 kcal mol-1), and the formation of a stable complex. The PLM- DNA complex with stable dynamics was further supported by different parameters including RMSD, RMSF, SASA, Rg, and the energy profile of interaction. This study provides an insight into the cytotoxic and genotoxic mechanism of PLM which can be a crucial step forward to exploit its therapeutic potential against several diseases including cancer.

Genome-Wide Analysis of Kidney Renal Cell Carcinoma: Exploring Differentially Expressed Genes for Diagnostic and Therapeutic Targets.

Kidney renal cell carcinoma (KIRC) is the most common type of renal cancer. Kidney malignancies have been ranked in the top 10 most frequently occurring cancers. KIRC is a prevalent malignancy with a poor prognosis. The disease has risen for the last 40 years, and robust biomarkers for KIRC are needed for precision/personalized medicine. In this bioinformatics study, we utilized genomic data of KIRC patients from The Cancer Genome Atlas for biomarker discovery. A total of 314 samples were used in this study. We identified many differentially expressed genes (DEGs) categorized as upregulated or downregulated. A protein-protein interaction network for the DEGs was then generated and analyzed using the Search Tool for the Retrieval of Interacting Genes plugin of Cytoscape. A set of 10 hub genes was selected based on the Maximum Clique Centrality score defined by the CytoHubba plugin. The elucidated set of genes, that is, CALCA, CRH, TH, CHAT, SLC18A3, FSHB, MYH6, CAV3, KCNA4, and GBX2, were then categorized as potential candidates to be explored as KIRC biomarkers. The survival analysis plots for each gene suggested that alterations in CHAT, CAV3, CRH, MYH6, SLC18A3, and FSHB resulted in decreased survival of KIRC patients. In all, the results suggest that genomic alterations in selected genes can be explored to inform biomarker discovery and for therapeutic predictions in KIRC.

Identifying promising GSK3ß inhibitors for cancer management: a computational pipeline combining virtual screening and molecular dynamics simulations.

Glycogen synthase kinase-3 (GSK3ß), a serine/threonine protein kinase, has been discovered as a novel target for anticancer drugs. Although GSK3ß is involved in multiple pathways linked to the etiology of various cancers, no specific GSK3ß inhibitor has been authorized for cancer therapy. Most of its inhibitors have toxicity effects therefore, there is a need to develop safe and more potent inhibitors. In this study, a library of 4,222 anti-cancer compounds underwent rigorous computational screening to identify potential candidates for targeting the binding pocket of GSK3ß. The screening process involved various stages, including docking-based virtual screening, physicochemical and ADMET analysis, and molecular dynamics simulations. Ultimately, two hit compounds, BMS-754807 and GSK429286A, were identified as having high binding affinities to GSK3ß. BMS-754807 and GSK429286A exhibited binding affinities of -11.9, and -9.8 kcal/mol, respectively, which were greater than that of the positive control (-7.6 kcal/mol). Further, molecular dynamics simulations for 100 ns were employed to optimize the interaction between the compounds and GSK3ß, and the simulations demonstrated that the interaction was stable and consistent throughout the study. These hits were also anticipated to have good drug-like properties. Finally, this study suggests that BMS-754807 and GSK429286A may undergo experimental validation to evaluate their potential as cancer treatments in clinical settings.

In Silico Screening and Molecular Dynamics Simulation Studies in the Identification of Natural Compound Inhibitors Targeting the Human Norovirus RdRp Protein to Fight Gastroenteritis.

Norovirus (HNoV) is a leading cause of gastroenteritis globally, and there are currently no treatment options or vaccines available to combat it. RNA-dependent RNA polymerase (RdRp), one of the viral proteins that direct viral replication, is a feasible target for therapeutic development. Despite the discovery of a small number of HNoV RdRp inhibitors, the majority of them have been found to possess a little effect on viral replication, owing to low cell penetrability and drug-likeness. Therefore, antiviral agents that target RdRp are in high demand. For this purpose, we used in silico screening of a library of 473 natural compounds targeting the RdRp active site. The top two compounds, ZINC66112069 and ZINC69481850, were chosen based on their binding energy (BE), physicochemical and drug-likeness properties, and molecular interactions. ZINC66112069 and ZINC69481850 interacted with key residues of RdRp with BEs of -9.7, and -9.4 kcal/mol, respectively, while the positive control had a BE of -9.0 kcal/mol with RdRp. In addition, hits interacted with key residues of RdRp and shared several residues with the PPNDS, the positive control. Furthermore, the docked complexes showed good stability during the molecular dynamic simulation of 100 ns. ZINC66112069 and ZINC69481850 could be proven as potential inhibitors of the HNoV RdRp in future antiviral medication development investigations.

Frustration analysis of TBK1 missense mutations reported in ALS/FTD and cancer patients.

Tank-binding kinase 1 (TBK1) is a multifunctional kinase having essential roles in cellular processes, autophagy/mitophagy, and selective clearance of damaged proteins. More than 90 mutations in the TBK1 gene are linked with multiple cancer types, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Some of these missense mutations disrupt the abilities of TBK1 to dimerize, associate with the mitophagy receptor optineurin (OPTN), autoactivate, or catalyze phosphorylation. Some mutations may cause severe dysregulation of the pathway, while others induce a limited disruption. Here, we have studied those mutations reported in cancer, ALS and FTD, and subsequently investigated the effect of missense mutations on the structure and function of TBK1 for localized residual frustration change. Out of 33 ALS/FTD causing mutations and 28 oncogenic mutations, 10 mutations and 12 oncogenic mutations showed significant change in the residual frustration. The local frustration plays an important role in the conformation of protein structure in active and inactive kinases. Our analysis reports the change in residual frustration state, conformational change and effect on active and inactive TBK1 function due to ALS/FTD causing and oncogenic missense mutations. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03240-0.

Brain-Derived Neurotrophic Factor: A Connecting Link Between Nutrition, Lifestyle, and Alzheimer's Disease.

Brain-derived neurotrophic factor (BDNF) involving tropomyosin kinase B and low affinity p75 neurotropin receptors is the most abundant and researched neurotropins in mammal's brain. It is one of the potential targets for therapeutics in Alzheimer's disease (AD) owing to its key role in synaptic plasticity. Low levels of BDNF are implicated in the pathophysiology of neurological diseases including AD. However, a healthy lifestyle, exercise, and dietary modifications are shown to positively influence insulin regulation in the brain, reduce inflammation, and up-regulate the levels of BDNF, and are thus expected to have roles in AD. In this review, the relationship between BDNF, mental health, and AD is discussed. Insights into the interrelationships between nutrition, lifestyle, and environment with BDNF and possible roles in AD are also provided in the review. The review sheds light on the possible new therapeutic targets in neurodegenerative diseases.

Infection Dynamics of ATG8 in Leishmania: Balancing Autophagy for Therapeutics.

In many regions of the world, Leishmaniasis is a cause of substantial mortality and ailment. Due to impediment in available treatment, development of novel and effective treatments is indispensable. Significance of autophagy has been accentuated in infectious disease as well as in Leishmaniasis, and it is having capability to be manifested as a therapeutic target. By evincing autophagy as a novel therapeutic regime, this study emphasized on the critical role of ATG4.1-ATG8 and ATG5-ATG12 complexes in Leishmania species. The objective here was to identify ATG8 as a potential therapeutic target in Leishmania. R71T, P56E, R18P are the significant mutations which shows detrimental effect on ATG8 while Arg276, Arg73, Cys75 of ATG4.1 and Val88, Pro89, Glu116, Asn117, and Gly120 are interacting residues of ATG8. Along with this, we also bring into spotlight an enticing role of Thiabendazole derivatives that interferes with the survival mechanisms by targeting ATG8. Further, the study claims that thiabendazole can be a potential drug candidate to target autophagy process in the infectious disease Leishmaniasis.

Comparative analysis of web-based programs for single amino acid substitutions in proteins.

Single amino-acid substitution in a protein affects its structure and function. These changes are the primary reasons for the advent of many complex diseases. Analyzing single point mutations in a protein is crucial to see their impact and to understand the disease mechanism. This has given many biophysical resources, including databases and web-based tools to explore the effects of mutations on the structure and function of human proteins. For a given mutation, each tool provides a score-based outcomes which indicate deleterious probability. In recent years, developments in existing programs and the introduction of new prediction algorithms have transformed the state-of-the-art protein mutation analysis. In this study, we have performed a systematic study of the most commonly used mutational analysis programs (10 sequence-based and 5 structure-based) to compare their prediction efficiency. We have carried out extensive mutational analyses using these tools for previously known pathogenic single point mutations of five different proteins. These analyses suggested that sequence-based tools, PolyPhen2, PROVEAN, and PMut, and structure-based web tool, mCSM have a better prediction accuracy. This study indicates that the employment of more than one program based on different approaches should significantly improve the prediction power of the available methods.

Bioactive phytoconstituents as potent inhibitors of casein kinase-2: dual implications in cancer and COVID-19 therapeutics.

Casein kinase 2 (CK2) is a conserved serine/threonine-protein kinase involved in hematopoietic cell survival, cell cycle control, DNA repair, and other cellular processes. It plays a significant role in cancer progression and viral infection. CK2 is considered a potential drug target in cancers and COVID-19 therapy. In this study, we have performed a virtual screening of phytoconstituents from the IMPPAT database to identify some potential inhibitors of CK2. The initial filter was the physicochemical properties of the molecules following the Lipinski rule of five. Then binding affinity calculation, PAINS filter, ADMET, and PASS analyses followed by interaction analysis were carried out to discover nontoxic and better hits. Finally, two compounds, stylopine and dehydroevodiamines with appreciable affinity and specific interaction towards CK2, were identified. Their time-evolution analyses were carried out using all-atom molecular dynamics simulation, principal component analysis and free energy landscape. Altogether, we propose that stylopine and dehydroevodiamines can be further explored in in vitro and in vivo settings to develop anticancer and antiviral therapeutics.

Insights into the Antibacterial Activity of Prolactin-Inducible Protein against the Standard and Environmental MDR Bacterial Strains.

Background: Prolactin inducible protein (PIP) is a small secretary glycoprotein present in most biological fluids and contributes to various cellular functions, including cell growth, fertility, antitumor, and antifungal activities. Objectives: The present study evaluated the antibacterial activities of recombinant PIP against multiple broad-spectrum MDR bacterial strains. Methods: The PIP gene was cloned, expressed and purified using affinity chromatography. Disk diffusion, broth microdilution, and growth kinetic assays were used to determine the antibacterial activities of PIP. Results: Disk diffusion assay showed that PIP has a minimum and maximum zone of inhibition against E. coli and P. aeruginosa, respectively, compared to the reference drug ampicillin. Furthermore, growth kinetics studies also suggested that PIP significantly inhibited the growth of E. coli and P. aeruginosa. The minimum inhibitory concentration of PIP was 32 µg/mL for E. coli (443), a standard bacterial strain, and 64 µg/mL for Bacillus sp. (LG1), an environmental multidrug-resistant (MDR) strain. The synergistic studies of PIP with ampicillin showed better efficacies towards selected bacterial strains having MDR properties. Conclusion: Our findings suggest that PIP has a broad range of antibacterial activities with important implications in alleviating MDR problems.

PyPAn: An Automated Graphical User Interface for Protein Sequence and Structure Analyses.

BACKGROUND: Protein sequence and structure analyses have been essential components of bioinformatics and structural biology. They provide a deeper insight into the physicochemical properties, structure, and subsequent functions of a protein. Advanced computational approaches and bioinformatics utilities help solve several issues related to protein analysis. Still, beginners and non-professional may struggle when encountering a wide variety of computational tools and the sheer number of input parameter variables required by each tool. METHODS: We introduce a free-to-access graphical user interface (GUI) named PyPAn 'Python-based Protein Analysis' for varieties of protein sequence/structure analyses. PyPAn serves as a universal platform to analyze protein sequences, structure, and their properties. PyPAn facilitates onboard analysis of each task in just a single click. It can be used to calculate the physicochemical properties, including instability index and molar extinction coefficient, for a protein. PyPAn is one of the few computational tools that allow users to generate a Ramachandran plot and calculate solvent accessibility and the radius of gyration (Rg) of proteins at once. In addition, it can refine the protein model along with computation and minimization of its energy. RESULTS: PyPAn can generate a recommendation for an appropriate structure modelling method to employ for a query protein sequence. PyPAn is one of the few, if not the only, Python-based computational GUI tools with an array of options for the user to employ as they see fit. CONCLUSION: PyPAn aims to unify many successful academically significant proteomic applications and is freely available for academic and industrial research uses at https://hassanlab.org/pypan.

Targeting Cytotoxin-Associated Antigen A, a Virulent Factor of Helicobacter pylori-Associated Gastric Cancer: Structure-Based In Silico Screening of Natural Compounds.

Gastric cancer is the fifth most frequent cancer and the third major cause of mortality worldwide. Helicobacter pylori, a bacterial infection linked with GC, injects the cytotoxin-associated antigen A (CagA; an oncoprotein) into host cells. When the phosphorylated CagA protein enters the cell, it attaches to other cellular components, interfering with normal cellular signaling pathways. CagA plays an important role in the progression of GC by interacting with phosphatidylserine of the host cell membrane. Therefore, disrupting the CagA-phosphatidylserine connection using small molecules appears to be a promising therapeutic approach. In this report, we screened the natural compounds from ZINC database against the CagA protein using the bioinformatics tools. Hits were initially chosen based on their physicochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics, as well as other drug-like characteristics. To locate safe and effective hits, the PAINS filter, binding affinities estimation, and interaction analysis were used. Three compounds with high binding affinity and specificity for the CagA binding pocket were discovered. The final hits, ZINC153731, ZINC69482055, and ZINC164387, were found to bind strongly with CagA protein, with binding energies of -11.53, -10.67, and -9.21 kcal/mol, respectively, which were higher than that of the control compound (-7.25 kcal/mol). Further, based on binding affinity and interaction pattern, two leads (ZINC153731, ZINC69482055) were chosen for molecular dynamics (MD) simulation analysis. MD results showed that they displayed stability in their vicinity at 100 ns. This study suggested that these compounds could be used as possible inhibitors of CagA protein in the fight against GC. However, additional benchwork tests are required to validate them as CagA protein inhibitors.