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Monkeypox virus (MPXV) core cysteine proteinase (CCP) is one of the major drug targets used to examine the inhibitory action of chemical moieties. In this study, an in silico technique was applied to screen 1395 anti-infective compounds to find out the potential molecules against the MPXV-CCP. The top five hits were selected after screening and processed for exhaustive docking based on the docked score of ≤ -9.5 kcal/mol. Later, the top three hits based on the exhaustive-docking score and interaction profile were selected to perform MD simulations. The overall RMSD suggested that two compounds, SC75741 and ammonium glycyrrhizinate, showed a highly stable complex with a standard deviation of 0.18 and 0.23 nm, respectively. Later, the MM/GBSA binding free energies of complexes showed significant binding strength with ΔG TOTAL  from -21.59 to -15 kcal/mol. This report reported the potential inhibitory activity of SC75741 and ammonium glycyrrhizinate against MPXV-CCP by competitively inhibiting the binding of the native substrate., Competing Interests: Declarations. Competing interest: The authors declare no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The oral pathogen Fusobacterium nucleatum has recently been associated with an elevated risk of colorectal cancer (CRC), endometrial metastasis, chemoresistance, inflammation, metastasis, and DNA damage, along with several other diseases. This study aimed to explore the disruption of protein machinery of F. nucleatum via inhibition of elongation factor thermo unstable (Ef-Tu) protein, through natural products. No study on Ef-Tu inhibition by natural products or in Fusobacterium spp. exists till todate. Ef-Tu is an abundant specialized drug target in bacteria that varies from human Ef-Tu. Elfamycins target Ef-Tu and hence, Enacyloxin IIa was used to generate pharmacophore for virtual screening of three natural product libraries, Natural Product Activity and Species Source (NPASS) (n = 30000 molecules), Tibetan medicinal plant database (n = 54 molecules) and African medicinal plant database (n > 6000 molecules). Peptaibol Septocylindrin B (NPC141050), Hirtusneanoside, and ZINC95486259 were prioritized from these libraries as potential therapeutic candidates. ADMET profiling was done for safety assessment, physiological-based pharmacokinetic modeling in human and mouse for getting insight into drug interaction with body tissues and molecular dynamics was used to assess stability of the best hit NPC141050 (Septocylindrin B). Based on the promising results, we propose further in vitro, in vivo and pharmacokinetic testing on the lead Septocylindrin B, for possible translation into therapeutic interventions., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethics approval and consent to participate: Not applicable. Consent for publication: All authors approved manuscript for publication in current form., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, posing significant challenges and economic burdens on healthcare systems. Gut microbiota metabolites have shown promise in cancer treatment, but the specific active metabolites and their key targets remain unclear. This study employed a network pharmacology-based approach to identify potent metabolites of gut microbiota and their key targets. Active metabolites produced by gut microbiota were retrieved using the database gutMGene, and targets associated with these metabolites were identified using the Swiss Target Prediction tool. HCC-related targets were obtained from the GeneCards database, and overlapping targets were selected through a Venn diagram tool. An integrated metabolites-target-pathway network was analyzed to identify active inhibitors against HCC, including p -cresol glucuronide, secoisolariciresinol, glycocholic acid, enterodiol, and citric acid. Molecular docking tests were performed to validate the findings and assess the binding affinity of the metabolites with their target proteins. The study identified AKT1, EGFR, ALB, and TNF genes as potential therapeutic targets against hepatic cancer. The metabolites, p -cresol glucuronide, secoisolariciresinol, glycocholic acid, enterodiol, and citric acid, exhibited significant binding affinity with their respective target proteins. The study also revealed multiple signaling pathways and biological processes associated with the metabolites, demonstrating their preventive effect against HCC. This research utilizes a network pharmacology-based approach to identify potent metabolites of gut microbiota and their key targets for the treatment of HCC. The findings were validated through molecular docking tests, providing a foundation for future studies on anti-HCC metabolites and their mechanisms of action. Furthermore, this study offers insights into the development of novel anti-HCC drugs utilizing gut microbiota metabolites., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Sehar Aslam et al.)

One of the emerging epidemic concerns is Monkeypox disease which is spreading globally. This disease is caused by the monkeypox virus (MPXV), with an increasing global incidence with an outbreak in 2022. One of the novel targets for monkeypox disease is thymidylate kinase, which is involved in pyrimidine metabolism. In this study, docking-based virtual screening and molecular dynamics techniques were employed in addition to the machine learning (ML) model to investigate the potential anti-viral natural small compounds to inhibit thymidylate kinase of MPXV. Several potential hits were identified through high-throughput virtual screening, and further top three candidates were selected, which ranked using the ML model. These three compounds were then examined under molecular dynamics simulation and MM/GBSA-binding free energy analysis. Among these, Chlorhexidine HCl showed high potential for binding to the thymidylate kinase with stable and consistent conformation with RMSD < 0.3 nm. The MM/GBSA analysis also showed the minimum binding free energy (ΔG TOTAL ) of -62.41 kcal/mol for this compound. Overall, this study used structure-based drug design complemented by machine learning-guided ligand-based drug design to screen potential hit compounds from the anti-viral natural compound database., Competing Interests: Declarations. Competing interests: None. Ethical approval: None to declare., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Cervical cancer originates in the cervix, the lower part of the uterus, and results from the uncontrolled growth of abnormal cervical cells, forming malignant tumours. It poses a major global health challenge, calling for innovative drug design strategies to enhance treatment outcomes., Method: In this study, we have screened the FDA-approved drug library against four proteins, MCM10, MCM6, DNA polymerase epsilon subunit-2, and TBK1, which are essential for DNA replication, DNA repair, and cellular signalling pathways, which are dysregulated in cervical cancer cells, leading to uncontrolled growth. We have used the multisampling algorithms for screening using HTVS, SP, and XP docking; identified 6- oxidopamine HBr (C8H12BrNO3), which is used to create a model of Parkinson's disease in animals, and obtained the docking score ranging from -5.057 to -8.871 Kcal/mol. The poses were filtered with MM\GBSA score ranging from -21.67 to -27.63 Kcal/mol. We performed QM-based DFT and pharmacokinetics studies and compared them with the standard values, suggesting that the compound can be used in cervical cancer proteins., Result: The P-L complex's interaction fingerprints have resulted in the most interacting residues, 4THR, 4SER, and 4LYS, showing the compound's interaction pattern., Conclusion: Further, the stability of 6-oxidopamine HBr in complex with each protein was evaluated with 100ns MD simulation in the SPC water model in a neutralised state to analyse the deviation, fluctuations, and intermolecular interactions that have proven the compound to have a better inhibitory effect against each protein and that it can be used for cervical cancer; however, experimental validation is suggested before human use., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Tuberculosis (TB), an infectious disease caused by the Mycobacterium tuberculosis (Mtb), has been responsible for the deaths of millions of individuals around the globe. A vital protein in viral pathogenesis known as resuscitation promoting factor (RpfB) has been identified as a potential therapeutic target of anti-tuberculosis drugs. This study offered an in silico process to examine possible RpfB inhibitors employing a computational drug design pipeline. In this study, a total of 1228 phytomolecules were virtually tested against the RpfB of Mtb. These phytomolecules were sourced from the NP-lib database of the MTi-OpenScreen server, and five top hits (ZINC000044404209, ZINC000059779788, ZINC000001562130, ZINC000014766825, and ZINC000043552589) were prioritized for compute intensive docking with dock score ≤ - 8.5 kcal/mole. Later, molecular dynamics (MD) simulation and principal component analysis (PCA) were used to validate these top five hits. In the list of these top five hits, the ligands ZINC000044404209, ZINC000059779788, and ZINC000043552589 showed hydrogen bond formation with the functional residue Glu 292 of the RpfB protein suggesting biological significance of the binding. The RMSD study showed stable protein-ligand complexes and higher conformational consistency for the ligands ZINC000014766825, and ZINC000043552589 with RMSD 3-4 Å during 100 ns MD simulation. The overall analysis performed in the study suggested promising binding of these compounds with the RpfB protein of the Mtb at its functional site, further experimental investigation is needed to validate the computational finding., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Lung Cancer is the one that causes more fatalities in the world compared to other cancers, and its uniqueness is that it can be found in both males and females. However, recent data has shown that males are more affected due to lifestyle habits like smoking, tobacco consumption and inhaling polluted air. The World Health Organization has kept lung cancer on its priority list as it causes 1.8 million deaths worldwide each year, and the predictions show that the cases are going to increase year by year, and by 2050, there can be 3.8 million new cases and 3.2 million deaths, and the global health system is not prepared for it. Also, finding drug candidates that can help shrink cancerous cells and lead to their death is essential to reduce global mortality. The system needs drug compounds that can inhibit multiple paths together not to enter drug resistance quickly and to reduce costs. Our study identified a compound named Variolin B (DB08694) that belongs to the organic compounds class of pyrrolopyridines. The identified compound can inhibit multiple proteins, drastically reducing the global burden. Variolin B was identified as a potential candidate against lung cancer using the multisampling algorithm such as HTVS, SP, and XP, followed by MM\GBSA calculations showing the docking score of -9.245 Kcal/mol to -5.92 Kcal/mol. Also, we have validated it with ADMET predictions and molecular fingerprinting to analyse the interaction patterns. Further, the study was extended to molecular dynamics simulations for 100 ns to understand the complex stability and simulative interactions. The complex's overall molecular dynamics simulation helped us understand that the identified candidate is stable with the lowest deviation and fluctuations.Communicated by Ramaswamy H. Sarma.

Campylobacter hyointestinalis is a causative agent of enteritis, proctitis, human gastroenteritis, and diarrhea. Reported transmission is from pigs to humans. Link with gastrointestinal carcinoma has also been established in non- Helicobacter pylori patients carrying this strain. The genome size of the strain LMG9260 is 1.8 MB with 1785 chromosomal and seven plasmid proteins. No therapeutic targets have been identified and reported in this bacterium. Therefore, subtractive computational screening of its genome was carried out for the purpose. In total, 31 such targets were mined and riboflavin synthase was utilized for screening natural product inhibitors against it. Among more than 30,000 screened natural compounds from the NPASS library, three (NPC472060, NPC33653, and NPC313886) were prioritized to have the potential to be developed into new antimicrobial drugs. Dynamics simulation assay along with other relevant parameters like absorption, toxicity, and distribution of the inhibiting compounds were also predicted and NPC33653 was identified as having the best drug-like properties among the prioritized compounds. Thus, it has potential to be pursued further for the inhibition of riboflavin synthesis in C. hyointestinalis for subsequent obstruction of its growth and survival.Communicated by Ramaswamy H. Sarma.

Breast cancer begins in the breast cells, mainly impacting women. It starts in the cells that line the milk ducts or lobules responsible for producing milk and can spread to nearby tissues and other body parts. In 2020, around 2.3 million women across the globe received a diagnosis, with an estimated 685,000 deaths. Additionally, 7.8 million women were living with breast cancer, making it the fifth leading cause of cancer-related deaths among women. The mutational changes, overexpression of drug efflux pumps, activation of alternative signalling pathways, tumour microenvironment, and cancer stem cells are causing higher levels of drug resistance, and one of the major solutions is to identify multitargeted drugs. In our research, we conducted a comprehensive screening using HTVS, SP, and XP, followed by an MM/GBSA computation of human-approved drugs targeting HER2/neu, BRCA1, PIK3CA, and ESR1. Our analysis pinpointed IRESSA (Gefitinib-DB00317) as a multitargeted inhibitor for these proteins, revealing docking scores ranging from -4.527 to -8.809 Kcal/mol and MM/GBSA scores between -49.09 and -61.74 Kcal/mol. We selected interacting residues as fingerprints, pinpointing 8LEU, 6VAL, 6LYS, 6ASN, 5ILE, and 5GLU as the most prevalent in interactions. Subsequently, we analysed the ADMET properties and compared them with the standard values of QikProp. We extended our study for DFT computations with Jaguar and plotted the electrostatic potential, HOMO and LUMO regions, and electron density, followed by a molecular dynamics simulation for 100 ns in water, showing an utterly stable performance, making it a suitable drug candidate. IRESSA is FDA-approved for lung cancer, which shares some pathways with breast cancers, clearing the hurdles of multitargeted drugs against breast and lung cancer. This has the potential to be groundbreaking; however, more studies are needed to concreate IRESSA's role.

Lung Cancer is the topmost death causing cancer and results from smoking, air pollution, cigar, exposure to asbestos or radon-like substances, and genetic factors. The cases of Lung Cancer in south Asian developing nations are being seen most due to heavy pollution and unbalanced lifestyle and putting a considerable burden on healthcare systems. The Food and Drug Administration of the USA has approved almost 100 drugs against SCLC and NSLC and a few drugs that are given to minimise the side effect of anticancer drugs. However, the drugs are shown to be resistant at significantly higher stages and non-affective on cancerous cells and have long-term side effects due to designing the drug by keeping one protein/gene target while designing or repurposing the drugs. In this study, we have taken five main lung cancer protein targets- Nerve growth factor protein (1SG1), Apoptosis inhibitor survivin (1XOX), Heat shock protein (3IUC), Protein tyrosine phosphate (3ZM3), Aldo-keto reductase (4XZL) and screened the complete prepared Drug Bank library of 155888 compounds and identified Variolin B (DB08694) as a multitargeted inhibitor against lung cancer using HTVS, SP and XP sampling algorithms followed by MM\GBSA calculation to sort the best pose. Variolin B is a natural marine antitumor and antiviral compound, so we analysed the ADMET properties and interaction patterns and then simulated all five P-L complexes for 100 ns in water using the NPT ensemble to check its selves against lung cancer. The docking results, ADMET and fingerprints have shown a good performance, and RMSD and RMSF results were with least deviation and fluctuations (<2Å) and produced a huge contact with other residues making the complex stable. The complexes initially fluctuated and deviated due to changes in the solute medium and sudden heat and stabilise after a few ns. However, extensive experimental validation is required before human use.Communicated by Ramaswamy H. Sarma.

Kingella kingae is a Gram-negative bacterium that primarily causes pediatric infections such as septicemia, endocarditis, and osteoarticular infections. Its virulence is attributed to the outer membrane proteins having implications in bacterial adhesion, invasion, nutrition, and host tissue damage. TonB-dependent receptors (TBDRs) play an important role in nutrition and were previously implicated as vaccine targets in other bacteria. Therefore, we targeted the conserved β-barrel TBDR domain of these proteins for designing a vaccine construct that could elicit humoral and cellular immune responses. We used bioinformatic tools to mine TBDR-containing proteins from K. kingae ATCC 23330 and then predict B- and T-cell epitopes from their conserved β-barrel TDR domain. A chimeric vaccine construct was designed using three antigenic epitopes, covering >98% of the world population and capable of inciting humoral and adaptive immune responses. The final construct elicited a robust immune response. Docking and dynamics simulation showed good binding affinity of the vaccine construct to various receptors of the immune system. Additionally, the vaccine was predicted to be safe and non-allergenic, making it a promising candidate for further development. In conclusion, our study demonstrates the potential of immunoinformatics approaches in designing chimeric vaccines against K. kingae infections. The chimeric vaccine we designed can serve as a blueprint for future experimental studies to develop an effective vaccine against this pathogen, which can serve as a potential strategy to prevent K. kingae infections., Competing Interests: Authors IA and ZB were employed by Alpha Genomics Private Limited. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mashraqi, Alzamami, Alturki, Almasaudi, Ahmed, Alshamrani and Basharat.)

One of the most important breakthroughs in healthcare is the development of vaccines. The life cycle and its gene expression in the numerous virus-associated disorders must be considered when choosing the target vaccine antigen for Epstein-Barr virus (EBV). The vaccine candidate used in the current study will also be effective against all other herpesvirus strains, based on the conservancy study, which verified that the protein is present in all herpesviruses. From the screening, two B-cell epitopes, four MHC-I, and five MHC-II restricted epitopes were chosen for further study. The refined epitopes indicated 70.59% coverage of the population in Malaysia and 93.98% worldwide. After removing the one toxin (PADRE) from the original vaccine design, it was projected that the new vaccine would not be similar to the human host and would instead be antigenic, immunogenic, non-allergenic, and non-toxic. The vaccine construct was stable, thermostable, soluble, and hydrophilic. The immunological simulation projected that the vaccine candidate would be subject to a long-lasting active adaptive response and a short-lived active innate response. With IgM concentrations of up to 450 cells per mm 3 and active B-cell concentrations of up to 400 cells per mm 3 , the B-cells remain active for a considerable time. The construct also discovered other conformational epitopes, improving its ability to stimulate an immune response. This suggests that, upon injection, the epitope will target the B-cell surface receptors and elicit a potent immune response. Furthermore, the discotope analysis confirmed that our conformational B-cell epitope was not displaced during the design. Lastly, the docking complex was stable and exhibited little deformability under heat pressure. These computational results are very encouraging for future testing of our proposed vaccine, which may potentially help in the management and prevention of EBV infections worldwide.

Molecular mimicry, a phenomenon in which microbial or environmental antigens resemble host antigens, has been proposed as a potential trigger for autoimmune responses. In this study, we employed a bioinformatics approach to investigate the role of molecular mimicry in Clostridioides difficile -caused infections and the induction of autoimmune disorders due to this phenomenon. Comparing proteomes of host and pathogen, we identified 23 proteins that exhibited significant sequence homology and were linked to autoimmune disorders. The disorders included rheumatoid arthritis, psoriasis, Alzheimer's disease, etc., while infections included viral and bacterial infections like HIV, HCV, and tuberculosis. The structure of the homologous proteins was superposed, and RMSD was calculated to find the maximum deviation, while accounting for rigid and flexible regions. Two sequence mimics (antigenic, non-allergenic, and immunogenic) of ≥10 amino acids from these proteins were used to design a vaccine construct to explore the possibility of eliciting an immune response. Docking analysis of the top vaccine construct C2 showed favorable interactions with HLA and TLR-4 receptor, indicating potential efficacy. The B-cell and T-helper cell activity was also simulated, showing promising results for effective immunization against C. difficile infections. This study highlights the potential of C. difficile to trigger autoimmunity through molecular mimicry and vaccine design based on sequence mimics that trigger a defensive response.

The coronaviridae family has caused the most destruction among all the viral families in modern sciences. It is one of the recently discovered and added members of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has caused the global pandemic and significant destruction worldwide. However, scientists worldwide have developed vaccines, which are being given to humans. The mutated strain of the virus has caused various uncertainties about whether the discovered drug and vaccines affect it. Even after the World Health Organization's approval for the vaccines, their effectiveness and protection ratio are still a major concern. At the community level, to this date, there is no medicine available to cure the patients. In this study, we have screened the vast library from Drug Bank and identified N-(4-Aminobutanoyl)-S-(4-methoxybenzyl)-L-cysteinylglycine (NSL-CG) that can work against two major targets of SARS CoV-2, replication-transcription and RNA dependent polymerase. Further, we have performed the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and molecular dynamics simulation of the compound with both proteins individually, giving us enough evidence that the said drugs can work against the two targets together. Inhibiting the action of any of both proteins may lead to retaining the virus, and having a dual-targeted drug can be an extra precise measure for this process. The NSL-CG is an experimental drug belonging to the peptidomimetics class included in the small group of drugs with a docking score of -9.079 kcal/mol with replication-transcription -7.885 kcal/mol with RNA-dependent polymerase. Hence, through the complete flowed study, the NSL-CG can be further experimentally validated in in-vitro and in-vivo conditions before human utilisation.Communicated by Ramaswamy H. Sarma.

Cervical cancer is a significant cause of morbidity and mortality in women worldwide. Despite the availability of effective therapies, the development of drug resistance and adverse side effects remain significant challenges in cervical cancer treatment. Thus, repurposing existing drugs as multitargeted therapies for cervical cancer is an attractive approach. In this study, we extensively screened the complete prepared FDA-approved drugs and identified the repurposing potential of taxifolin, a flavonoid with known antioxidant and anti-inflammatory properties, as a multitargeted therapy for cervical cancer. We performed a computational analysis using molecular docking with various sampling algorithms, namely HTVS, SP, and XP algorithms, for robust sampling pose and filtered with MM/GBSA analysis to determine the binding affinity of taxifolin with potential targets involved in cervical cancer, such as Symmetric Mad2 Dimer, replication initiation factor MCM10-ID, TPX2, DNA polymerase epsilon B-subunit, human TBK1, and alpha-v beta-8. We then conducted MD simulations to investigate the stability and conformational changes of the complex formed between taxifolin and the mentioned proteins. Our results suggest that taxifolin has a high binding affinity ranging from - 6.094 to - 9.558 kcal/mol, indicating its potential as a multitargeted therapy for cervical cancer. Furthermore, interaction fingerprints, pharmacokinetics and MD simulations revealed that the Taxifolin-target complexes remained stable over the simulation period, indicating that taxifolin may bind to the targets for an extended period. Our study suggests that taxifolin has the potential as a multitargeted therapy for cervical cancer, and further experimental studies are necessary to validate our findings., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Streptococcus pneumoniae contributes to a range of infections, including meningitis, pneumonia, otitis media, and sepsis. Infections by this bacterium have been associated with the phenomenon of molecular mimicry, which, in turn, may contribute to the induction of autoimmunity. In this study, we utilized a bioinformatics approach to investigate the potential for S. pneumoniae to incite autoimmunity via molecular mimicry. We identified 13 S. pneumoniae proteins that have significant sequence similarity to human proteins, with 11 of them linked to autoimmune disorders such as psoriasis, rheumatoid arthritis, and diabetes. Using in silico tools, we predicted the sequence as well as the structural homology among these proteins. Database mining was conducted to establish links between these proteins and autoimmune disorders. The antigenic, non-allergenic, and immunogenic sequence mimics were employed to design and validate an immune response via vaccine construct design. Mimic-based vaccine construct can prove effective for immunization against the S. pneumoniae infections. Immune response simulation and binding affinity was assessed through the docking of construct C8 to human leukocyte antigen (HLA) molecules and TLR4 receptor, with promising results. Additionally, these mimics were mapped as conserved regions on their respective proteins, suggesting their functional importance in S. pneumoniae pathogenesis. This study highlights the potential for S. pneumoniae to trigger autoimmunity via molecular mimicry and the possibility of vaccine design using these mimics for triggering defense response.

Campylobacter coli resides in the intestine of several commonly consumed animals, as well as water and soil. It leads to campylobacteriosis when humans eat raw/undercooked meat or come into contact with infected animals. A common manifestation of the infection is fever, nausea, headache, and diarrhea. Increasing antibiotic resistance is being observed in this pathogen. The increased incidence of C. coli infection, and post-infection complications like Guillain-Barré syndrome, make it an important pathogen. It is essential to find novel therapeutic targets and drugs against it, especially with the emergence of antibiotic-resistant strains. In the current study, genomes of 89 antibiotic-resistant strains of C. coli were downloaded from the PATRIC database. Potent drug targets (n = 36) were prioritized from the core genome (n = 1,337 genes) of this species. Riboflavin synthase was selected as a drug target and pharmacophore-based virtual screening was performed to predict its inhibitors from the NPASS (n =  ~ 30,000 compounds) natural product library. The top three docked compounds (NPC115144, NPC307895, and NPC470462) were selected for dynamics simulation (for 50 ns) and ADMET profiling. These identified compounds appear safe for targeting this pathogen and can be further validated by experimental analysis before clinical trials., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The emergence of novel variants of SARS-CoV-2 and their abilities to evade the immune response elicited through presently available vaccination makes it essential to recognize the mechanisms through which SARS-CoV-2 interacts with the human immune response. It is essential not only to comprehend the infection mechanism of SARS-CoV-2 but also for the generation of effective and reliable vaccines against COVID-19. The effectiveness of the vaccine is supported by the adaptive immune response, which mainly consists of B and T cells, which play a critical role in deciding the prognosis of the COVID-19 disease. T cells are essential for reducing the viral load and containing the infection. A plethora of viral proteins can be recognized by T cells and provide a broad range of protection, especially amid the emergence of novel variants of SARS-CoV-2. However, the hyperactivation of the effector T cells and reduced number of lymphocytes have been found to be the key characteristics of the severe disease. Notably, excessive T cell activation may cause acute respiratory distress syndrome (ARDS) by producing unwarranted and excessive amounts of cytokines and chemokines. Nevertheless, it is still unknown how T-cell-mediated immune responses function in determining the prognosis of SARS-CoV-2 infection. Additionally, it is unknown how the functional perturbations in the T cells lead to the severe form of the disease and to reduced protection not only against SARS-CoV-2 but many other viral infections. Hence, an updated review has been developed to understand the involvement of T cells in the infection mechanism, which in turn determines the prognosis of the disease. Importantly, we have also focused on the T cells' exhaustion under certain conditions and how these functional perturbations can be modulated for an effective immune response against SARS-CoV-2. Additionally, a range of therapeutic strategies has been discussed that can elevate the T cell-mediated immune response either directly or indirectly.

Colorectal cancer (CRC) ranks third among all cancers in terms of prevalence. There is growing evidence that gut microbiota has a role in the development of colorectal cancer. Fusobacterium nucleatum is overrepresented in the gastrointestinal tract and tumor microenvironment of patients with CRC. This suggests the role of F. nucleatum as a potential risk factor in the development of CRC. Hence, we aimed to explore whole genomes of F. nucleatum strains related to CRC to predict potential therapeutic markers through a pan-genome integrated subtractive genomics approach. In the current study, we identified 538 proteins as essential for F. nucleatum survival, 209 non-homologous to a human host, and 12 as drug targets. Eventually, riboflavin synthase (RiS) was selected as a therapeutic target for further processing. Three different inhibitor libraries of lead-like natural products, i.e., cyanobactins (n = 237), streptomycins (n = 607), and marine bacterial secondary metabolites (n = 1226) were screened against it. After the structure-based study, three compounds, i.e., CMNPD3609 (−7.63) > Malyngamide V (−7.03) > ZINC06804365 (−7.01) were prioritized as potential inhibitors of F. nucleatum. Additionally, the stability and flexibility of these compounds bound to RiS were determined via a molecular dynamics simulation of 50 ns. Results revealed the stability of these compounds within the binding pocket, after 5 ns. ADMET profiling showed compounds as drug-like, non-permeable to the blood brain barrier, non-toxic, and HIA permeable. Pan-genomics mediated drug target identification and the virtual screening of inhibitors is the preliminary step towards inhibition of this pathogenic oncobacterium and we suggest mouse model experiments to validate our findings.

Dengue fever (DF) continues to be one of the tropical and subtropical health concerns. Its prevalence tends to increase in some places in these regions. This disease is caused by the dengue virus (DENV), which is transmitted through the mosquitoes Aedes aegypti and A. albopictus . The treatment of DF to date is only supportive and there is no definitive vaccine to prevent this disease. The non-structural DENV protein, RNA-dependent RNA Polymerase (RdRp), is involved in viral replication. The RdRp-derived peptides can be used in the construction of a universal dengue vaccine. These peptides can be utilized as epitopes to induce immunity. This study was an in silico evaluation of the affinity of the potential epitope for the universal dengue vaccine to dendritic cells and the bonds between the epitope and the dendritic cell receptor. The peptide sequence MGKREKKLGEFGKAKG generated from dengue virus subtype 2 (DENV-2) RdRp was antigenic, did not produce allergies, was non-toxic, and had no homology with the human genome. The potential epitope-based vaccine MGKREKKLGEFGKAKG binds stably to dendritic cell receptors with a binding free energy of -474,4 kcal/mol. This epitope is anticipated to induce an immunological response and has the potential to serve as a universal dengue virus vaccine candidate.

Background: Little attention has been given to the development of lower respiratory tract infections (LRTIs) in patients with pulmonary tuberculosis (PTB) during their anti-tuberculosis (anti-TB) treatment and how that might affect patients' health status. Here, the prevalence and etiologies of other LRTIs in a cohort of PTB patients were determined, and the clinical features and outcomes were described., Methods: Adult patients with PTB between 2015 and 2020 were recruited and monitored during their anti-TB treatment for the presence of LRTIs. Clinical data were retrospectively collected from patients' medical records., Results: Data from 76 PTB patients (57 [75%] males) were reviewed. The median age was 61.0 (interquartile range 83.5-35.5) years, and other LRTIs were detected in 45 (59.2%) PTB patients. Of the 126 episodes of LRTIs, 84 (66.7%) were due to bacterial infections, 37 (29.4%) were due to fungal infections, and 5 (3.9%) were due to viral infections. The development of LRTIs was significantly more common in older ( P = 0.012) and hypertensive patients with PTB ( P = 0.019). Patients with PTB and LRTIs experienced significantly more frequent extrapulmonary infections ( P = 0.0004), bloodstream infections ( P = 0.001), intensive care unit stays ( P = 0.001), and invasive mechanical ventilation use ( P = 0.03) than patients who did not develop LRTI., Conclusions: The identification of host-related risk factors for LRTI development among patients with PTB could be used to develop a prediction model for LRTI development. Hence, initiating antimicrobials early, in parallel with appropriate anti-TB treatment, may mitigate PTB-related health and economic consequences., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Annals of Thoracic Medicine.)

Tuberculosis (TB) caused by the bacterial pathogen Mycobacterium tuberculosis ( Mtb ) remains a threat to mankind, with over a billion of deaths in the last two centuries. Recent advancements in science have contributed to an understanding of Mtb pathogenesis and developed effective control tools, including effective drugs to control the global pandemic. However, the emergence of drug resistant Mtb strains has seriously affected the TB eradication program around the world. There is, therefore, an urgent need to develop new drugs for TB treatment, which has grown researchers' interest in small molecule-based drug designing and development. The small molecules-based treatments hold significant potential to overcome drug resistance and even provide opportunities for multimodal therapy. In this context, various natural and synthetic flavonoids were reported for the effective treatment of TB. In this review, we have summarized the recent advancement in the understanding of Mtb pathogenesis and the importance of both natural and synthetic flavonoids against Mtb infection studied using in vitro and in silico methods. We have also included flavonoids that are able to inhibit the growth of non-tubercular mycobacterial organisms. Hence, understanding the therapeutic properties of flavonoids can be useful for the future treatment of TB.

Pyridine derivatives are the most common and significant heterocyclic compounds, which show their fundamental characteristics to various pharmaceutical agents and natural products. Pyridine derivatives possess several pharmacological properties and a broad degree of structural diversity that is most valuable for exploring novel therapeutic agents. These compounds have an extensive range of biological activities such as antifungal, antibacterial, anticancer, anti-obesity, anti-inflammatory, antitubercular, antihypertensive, antineuropathic, antihistaminic, antiviral activities, and antiparasitic. The potent therapeutic properties of pyridine derivatives allow medicinal chemists to synthesize novel and effective chemotherapeutic agents. Consequently, the imperative objective of this comprehensive review is to summarize and investigate the literature regarding recent advancements in pyridine-based heterocycles to treat several kinds of cancer. Furthermore, the performances of pyridine derivatives were compared with some standard drugs, including etoposide, sorafenib, cisplatin, and triclosan, against different cancer cell lines. We hope this study will support the new thoughts to pursue the most active and less toxic rational designs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

For the last few years, the world has been going through a difficult time, and the reason behind this is severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), one of the significant members of the Coronaviridae family. The major research groups have shifted their focus towards finding a vaccine and drugs against SARS-CoV-2 to reduce the infection rate and save the life of human beings. Even the WHO has permitted using certain vaccines for an emergency attempt to cut the infection curve down. However, the virus has a great sense of mutation, and the vaccine's effectiveness remains questionable. No natural medicine is available at the community level to cure the patients for now. In this study, we have screened the vast library of experimental drugs of Drug Bank with Schrodinger's maestro by using three algorithms: high-throughput virtual screening (HTVS), standard precision, and extra precise docking followed by Molecular Mechanics/Generalized Born Surface Area (MMGBSA). We have identified 3-(7-diaminomethyl-naphthalen-2-YL)-propionic acid ethyl ester and Thymidine-5'-thiophosphate as potent inhibitors against the SARS-CoV-2, and both drugs performed impeccably and showed stability during the 100 ns molecular dynamics simulation. Both of the drugs are among the category of small molecules and have an acceptable range of ADME properties. They can be used after their validation in in-vitro and in-vivo conditions.

It is well-acknowledged that 'combination therapy' of antibiotics is indispensable for the treatment of patients suffering from serious bacterial infections. Therefore, it is of interest to collect data from the in vitro tests using 'rifampicin-cefotaxime' and 'rifampicin-tetracycline' combination regimens against multi drug resistant Escherichia coli and Klebsiella pneumoniae strains of nosocomial source in order to determine the effectiveness of the combination therapy. The minimum inhibitory concentration (MIC) values for cefotaxime, tetracycline and rifampicin antibiotics were found to be comparatively high for each of the antibiotics when given individually. However, carefully prepared combination-regimens exhibited significant inhibitory effect on the same bacterial isolates. DNA fragmentation study confirmed that 'rifampicin-cefotaxime' and 'rifampicin-tetracycline' combination-regimens could cause breakage of the bacterial DNA. Thus, we show that combination-regimens namely, 'rifampicin-cefotaxime' and 'rifampicin-tetracycline' were found to be capable of maintaining rifampicin susceptibility in the E. coli and K. pneumoniae strains. However, this susceptibility was not maintained by only rifampicin. More data using animal model experiments are needed for confirming and deriving translational benefits from these findings in future., Competing Interests: The authors declare no conflict of Interest., (© 2022 Biomedical Informatics.)

Campylobacter ureolyticus is a Gram-negative, anaerobic, non-spore-forming bacteria that causes gastrointestinal infections. Being the most prevalent cause of bacterial enteritis globally, infection by this bacterium is linked with significant morbidity and mortality in children and immunocompromised patients. No information on pan-therapeutic drug targets for this species is available yet. In the current study, a pan-genome analysis was performed on 13 strains of C. ureolyticus to prioritize potent drug targets from the identified core genome. In total, 26 druggable proteins were identified using subtractive genomics. To the best of the authors' knowledge, this is the first report on the mining of drug targets in C. ureolyticus . UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) was selected as a promiscuous pharmacological target for virtual screening of two bacterial-derived natural product libraries, i.e., postbiotics ( n = 78) and streptomycin ( n = 737) compounds. LpxC inhibitors from the ZINC database ( n = 142 compounds) were also studied with reference to LpxC of C. ureolyticus . The top three docked compounds from each library (including ZINC26844580, ZINC13474902, ZINC13474878, Notoginsenoside St-4, Asiaticoside F, Paraherquamide E, Phytoene, Lycopene, and Sparsomycin) were selected based on their binding energies and validated using molecular dynamics simulations. To help identify potential risks associated with the selected compounds, ADMET profiling was also performed and most of the compounds were considered safe. Our findings may serve as baseline information for laboratory studies leading to the discovery of drugs for use against C. ureolyticus infections.

The coronaviruses belong to the Coronaviridae family, and one such member, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is causing significant destruction around the world in the form of a global pandemic. Although vaccines have been developed, their effectiveness and level of protection is still a major concern, even after emergency approval from the World Health Organisation (WHO). At the community level, no natural medicine is currently available as a cure. In this study, we screened the vast library from Drug Bank and identified Hemi-Babim and Fenoterol as agents that can work against SARS-CoV-2. Furthermore, we performed molecular dynamics (MD) simulation for both compounds with their respective proteins, providing evidence that the said drugs can work against the MPro and papain-like protease, which are the main drug targets. Inhibiting the action of these targets may lead to retaining the virus. Fenoterol is a beta-2 adrenergic agonist used for the symptomatic treatment of asthma as a bronchodilator and tocolytic. In this study, Hemi-Babim and Fenoterol showed good docking scores of -7.09 and -7.14, respectively, and performed well in molecular dynamics simulation studies. Re-purposing the above medications has huge potential, as their effects are already well-proven and under public utilisation for asthma-related problems. Hence, after the comprehensive pipeline of molecular docking, MMGBSA, and MD simulation studies, these drugs can be tested in-vivo for further human utilisation.

Klebsiella aerogenes is a Gram-negative bacterium which has gained considerable importance in recent years. It is involved in 10% of nosocomial and community-acquired urinary tract infections and 12% of hospital-acquired pneumonia. This organism has an intrinsic ability to produce inducible chromosomal AmpC beta-lactamases, which confer high resistance. The drug resistance in K. aerogenes has been reported in China, Israel, Poland, Italy and the United States, with a high mortality rate (~50%). This study aims to combine immunological approaches with molecular docking approaches for three highly antigenic proteins to design vaccines against K. aerogenes . The synthesis of the B-cell, T-cell (CTL and HTL) and IFN-γ epitopes of the targeted proteins was performed and most conserved epitopes were chosen for future research studies. The vaccine was predicted by connecting the respective epitopes, i.e., B cells, CTL and HTL with KK, AAY and GPGPG linkers and all these were connected with N-terminal adjuvants with EAAAK linker. The humoral response of the constructed vaccine was measured through IFN-γ and B-cell epitopes. Before being used as vaccine candidate, all identified B-cell, HTL and CTL epitopes were tested for antigenicity, allergenicity and toxicity to check the safety profiles of our vaccine. To find out the compatibility of constructed vaccine with receptors, MHC-I, followed by MHC-II and TLR4 receptors, was docked with the vaccine. Lastly, in order to precisely certify the proper expression and integrity of our construct, in silico cloning was carried out. Further studies are needed to confirm the safety features and immunogenicity of the vaccine.

Vibrio cholerae causes the diarrheal disease cholera which affects millions of people globally. The outer membrane protein U (OmpU) is the outer membrane protein that is most prevalent in V. cholerae and has already been recognized as a critical component of pathogenicity involved in host cell contact and as being necessary for the survival of pathogenic V. cholerae in the host body. Computational approaches were used in this study to screen a total of 37,709 natural compounds from the traditional Chinese medicine (TCM) database against the active site of OmpU. Following a sequential screening of the TCM database, we report three lead compounds-ZINC06494587, ZINC85510056, and ZINC95910434-that bind strongly to OmpU, with binding affinity values of -8.92, -8.12, and -8.78 kcal/mol, which were higher than the control ligand (-7.0 kcal/mol). To optimize the interaction, several 100 ns molecular dynamics simulations were performed, and the resulting complexes were shown to be stable in their vicinity. Additionally, these compounds were predicted to have good drug-like properties based on physicochemical properties and ADMET assessments. This study suggests that further research be conducted on these compounds to determine their potential use as cholera disease treatment.

The goal of this study was to investigate whether Ducrosia flabellifolia and Savignya parviflora methanol extract the have effect on colon and prostate cancer cell lines. Analysis of total content of phenolics and flavonoids of each plant extract was carried out. Cytotoxic effect, cell cycle analysis, induction of apoptosis and gene expression of Bcl-2 and Bax genes were studied. Obtained results indicated that, the plant extracts exhibit growth inhibition of used cancer cell lines and induced apoptosis as well as arresting of cell cycle. At the molecular level, changes in gene expression were detected via qPCR and confirmed by western blotting. The exhibited anticancer potentialities of plant extracts against utilized cancer cell lines are due to its containing bioactive compounds. Further detailed isolation, fractionation and characterization of bioactive compounds are needed.

Severe acute respiratory viral infections are frequently associated with multiple organ failure, including acute kidney damage. The present study aimed to investigate the associated influence of COVID-19 on renal function in patients admitted to the intensive care unit in Asir region, Saudi Arabia. Thirty patients infected with COVID-19 who were referred to the intensive care unit during November and October 2020 at Asir central hospital, Asir region, Saudi Arabia were recruited. The age of patients ranged between 30 and 90 years old. Renal function tests exhibited dramatic changes in the renal biomarkers in patients with COVID-19. Blood urea levels in COVID-19 patients were significantly higher than in the control group. In addition, significantly lower albumin levels with abnormally decreased total protein levels were found in COVID-19 patients. Among the different electrolytes analyzed, a significantly lower calcium level was observed in COVID-19 patients' groups than in the controls. Renal function tests for COVID-19-infected ICU patients revealed significant changes, indicating the major impact of COVID-19 on kidney function. Monitoring renal function tests may assist in the early prognosis of COVID-19 patients. It is, therefore, crucial to increase the understanding of renal function tests in COVID-19 patients who were admitted to the hospital before their condition deteriorated.

The Food and Drug Administration (FDA) approved a new class of anti-diabetic medication (a sodium-glucose co-transporter 2 (SGLT2) inhibitor) in 2013. However, SGLT2 inhibitor drugs are under evaluation due to their associative side effects, such as urinary tract and genital infection, urinary discomfort, diabetic ketosis, and kidney problems. Even clinicians have difficulty in recommending it to diabetic patients due to the increased probability of urinary tract infection. In our study, we selected natural SGLT2 inhibitors, namely acerogenin B, formononetin, (-)-kurarinone, (+)-pteryxin, and quinidine, to explore their potential against an emerging uropathogenic bacterial therapeutic target, i.e., FimH. FimH plays a critical role in the colonization of uropathogenic bacteria on the urinary tract surface. Thus, FimH antagonists show promising effects against uropathogenic bacterial strains via their targeting of FimH's adherence mechanism with less chance of resistance. The molecular docking results showed that, among natural SGLT2 inhibitors, formononetin, (+)-pteryxin, and quinidine have a strong interaction with FimH proteins, with binding energy (∆G) and inhibition constant (ki) values of -5.65 kcal/mol and 71.95 µM, -5.50 kcal/mol and 92.97 µM, and -5.70 kcal/mol and 66.40 µM, respectively. These interactions were better than those of the positive control heptyl α-d-mannopyranoside and far better than those of the SGLT2 inhibitor drug canagliflozin. Furthermore, a 50 ns molecular dynamics simulation was conducted to optimize the interaction, and the resulting complexes were found to be stable. Physicochemical property assessments predicted little toxicity and good drug-likeness properties for these three compounds. Therefore, formononetin, (+)-pteryxin, and quinidine can be proposed as promising SGLT2 inhibitors drugs, with add-on FimH inhibition potential that might reduce the probability of uropathogenic side effects.