Subtractive genomics study for the identification of therapeutic targets against Cronobacter sakazakii: A threat to infants.

Cronobacter sakazakii is an opportunistic pathogen that has been associated with severe infection in neonates such as necrotizing enterocolitis (NEC), neonatal meningitis, and bacteremia. This pathogen can survive in a relatively dry environment, especially in powdered infant formula (PIF). Unfortunately, conventional drugs that were once effective against C. sakazakii are gradually losing their efficacy due to rising antibiotic resistance. In this study, a subtractive genomic approach was followed in order to identify potential therapeutic targets in the pathogen. The whole proteome of the pathogen was filtered through a step-by-step process, which involved removing paralogous proteins, human homologs, sequences that are less essential for survival, proteins with shared metabolic pathways, and proteins that are located in cells other than the cytoplasmic membrane. As a result, nine novel drug targets were identified. Further, the analysis also unveiled that the FDA-approved drug Terbinafine can be repurposed against the Glutathione/l-cysteine transport system ATP-binding/permease protein CydC of C. sakazakii. Moreover, molecular docking and dynamics studies of Terbinafine and CydC suggested that this drug can be used to treat C. sakazakii infection in neonates. However, for clinical purposes further in vitro and in vivo studies are necessary.

Gut microbiome composition reveals the distinctiveness between the Bengali people and the Indigenous ethnicities in Bangladesh.

Ethnicity has a significant role in shaping the composition of the gut microbiome, which has implications in human physiology. This study intends to investigate the gut microbiome of Bengali people as well as several indigenous ethnicities (Chakma, Marma, Khyang, and Tripura) residing in the Chittagong Hill Tracts areas of Bangladesh. Following fecal sample collection from each population, part of the bacterial 16 s rRNA gene was amplified and sequenced using Illumina NovaSeq platform. Our findings indicated that Bangladeshi gut microbiota have a distinct diversity profile when compared to other countries. We also found out that Bangladeshi indigenous communities had a higher Firmicutes to Bacteroidetes ratio than the Bengali population. The investigation revealed an unclassified bacterium that was differentially abundant in Bengali samples while the genus Alistipes was found to be prevalent in Chakma samples. Further research on these bacteria might help understand diseases associated with these populations. Also, the current small sample-sized pilot study hindered the comprehensive understanding of the gut microbial diversity of the Bangladeshi population and its potential health implications. However, our study will help establish a basic understanding of the gut microbiome of the Bangladeshi population.

Subtractive genomics study of Xanthomonas oryzae pv. Oryzae reveals repurposable drug candidate for the treatment of bacterial leaf blight in rice.

BACKGROUND: Xanthomonas oryzae pv. oryzae is a plant pathogen responsible for causing one of the most severe bacterial diseases in rice, known as bacterial leaf blight that poses a major threat to global rice production. Even though several experimental compounds and chemical agents have been tested against X. oryzae pv. oryzae, still no approved drug is available. In this study, a subtractive genomic approach was used to identify potential therapeutic targets and repurposible drug candidates that could control of bacterial leaf blight in rice plants. RESULTS: The entire proteome of the pathogen underwent an extensive filtering process which involved removal of the paralogous proteins, rice homologs, non-essential proteins. Out of the 4382 proteins present in Xoo proteome, five hub proteins such as dnaA, dnaN, recJ, ruvA, and recR were identified for the druggability analysis. This analysis led to the identification of dnaN-encoded Beta sliding clamp protein as a potential therapeutic target and one experimental drug named [(5R)-5-(2,3-dibromo-5-ethoxy-4hydroxybenzyl)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid that can be repurposed against it. Molecular docking and 100 ns long molecular dynamics simulation suggested that the drug can form stable complexes with the target protein over time. CONCLUSION: Findings from our study indicated that the proposed drug showed potential effectiveness against bacterial leaf blight in rice caused by X. oryzae pv. oryzae. It is essential to keep in consideration that the procedure for developing novel drugs can be challenging and complicated. Even the most promising results from in silico studies should be validated through further in vitro and in vivo investigation before approval.

Gene silencing of Helicobacter pylori through newly designed siRNA convenes the treatment of gastric cancer.

BACKGROUND: Helicobacter pylori is a gastric pathogen that is responsible for causing chronic inflammation and increasing the risk of gastric cancer development. It is capable of persisting for decades in the harsh gastric environment because of the inability of the host to eradicate the infection. Several treatment strategies have been developed against this bacterium using different antibiotics. But the effectiveness of treating H. pylori has significantly decreased due to widespread antibiotic resistance, including an increased risk of gastric cancer. The small interfering RNAs (siRNA), which is capable of sequence-specific gene-silencing can be used as a new therapeutic approach for the treatment of a variety of such malignancies. In the current study, we rationally designed two siRNA molecules to silence the cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) genes of H. pylori for their significant involvement in developing cancer. METHODS: We selected a common region of all the available transcripts from different countries of CagA and VacA to design the siRNA molecules. The final siRNA candidate was selected based on the results from machine learning algorithms, off-target similarity, and various thermodynamic properties. RESULT: Further, we utilized molecular docking and all atom molecular dynamics (MD) simulations to assess the binding interactions of the designed siRNAs with the major components of the RNA-induced silencing complex (RISC) and results revealed the ability of the designed siRNAs to interact with the proteins of RISC complex in comparable to those of the experimentally reported siRNAs. CONCLUSION: These designed siRNAs should effectively silence the CagA and VacA genes of H. pylori during siRNA mediated treatment in gastric cancer.

Identification of repurposable drug targets in Mycoplasma pneumoniae using subtractive genomics, molecular docking and dynamics simulation.

Mycoplasma pneumoniae is a significant causative agent of community-acquired pneumonia, causing acute inflammation in the upper and lower respiratory tract as well as extrapulmonary syndromes. In particular, the elderly and infants are at greater risk of developing severe, life-threatening pneumonia caused by M. pneumoniae. Yet, the global increase in antimicrobial resistance against antibiotics for the treatment of M. pneumoniae infection highlights the urgent need to explore novel drug targets. To this end, bioinformatics approaches, such as subtractive genomics, can be employed to identify specific metabolic pathways and essential proteins unique to the pathogen that could be potential targets for new drugs. In this study, we implemented a subtractive genomics approach to identify 61 metabolic pathways and 42 essential proteins that are unique to M. pneumoniae. A subsequent screening in the DrugBank database revealed three druggable proteins with similarity to FDA-approved small-molecule drugs, and finally, the compound CHEBI:97093 was identified as a promising novel putative drug target. These findings can provide crucial insights for the development of highly effective drugs that selectively inhibit the pathogen-specific metabolic pathways, leading to better management and treatment of M. pneumoniae infections.

Investigation of pathogenic germline variants in gastric cancer and development of "GasCanBase" database.

BACKGROUND: Gastric cancer, which is also known as stomach cancer, can be influenced by both germline and somatic mutations. Non-synonymous Single Nucleotide Polymorphisms (nsSNPs) in germline have long been reported to play a pivotal role in cancer progression. AIM: The aim of this study is to examine the nsSNP in GC-associated genes. The study also aims to develop a database with extensive information regarding the nsSNPs in the GC-associated genes and their impacts. METHODS AND RESULTS: A total of 34,588 nsSNPs from 1,493,460 SNPs of the 40 genes were extracted from the available SNP database. Drug binding and energy minimization were examined by molecular docking and YASARA. To validate the existence of the germline CDH1 gene mutation (rs34466743) in the isolated blood DNA of gastric cancer (GC) patients, polymerase chain reaction (PCR) and DNA sequencing were performed. According to the results of the gene network analysis, 17 genes may interact with other types of cancer. A total of 11,363 nsSNPs were detected within the 40 GC genes. Among these, 474 nsSNPs were predicted to be damaging and 40 to be the most damaging. The SNPs in domain regions were thought to be strong candidates that alter protein functions. Our findings proposed that most of the selected nsSNPs were within the domains or motif regions. Free Energy Deviation calculation of protein structure pointed toward noteworthy changes in the structure of each protein that can demolish its natural function. Subsequently, drug binding confirmed the structural variation and the ineffectiveness of the drug against the mutant model in individuals with these germline variants. Furthermore, in vitro analysis of the rs34466743 germline variant from the CDH1 gene confirmed the strength and robustness of the pipeline that could expand the somatic alteration for causing cancer. In addition, a comprehensive gastric cancer polymorphism database named "GasCanBase" was developed to make data available to researchers. CONCLUSION: The findings of this study and the "GasCanBase" database may greatly contribute to our understanding of molecular epidemiology and the development of precise therapeutics for gastric cancer. GasCanBase is available at: https://www.gascanbase.com/.

Impact of highly deleterious non-synonymous polymorphisms on GRIN2A protein's structure and function.

GRIN2A is a gene that encodes NMDA receptors found in the central nervous system and plays a pivotal role in excitatory synaptic transmission, plasticity and excitotoxicity in the mammalian central nervous system. Changes in this gene have been associated with a spectrum of neurodevelopmental disorders such as epilepsy. Previous studies on GRIN2A suggest that non-synonymous single nucleotide polymorphisms (nsSNPs) can alter the protein's structure and function. To gain a better understanding of the impact of potentially deleterious variants of GRIN2A, a range of bioinformatics tools were employed in this study. Out of 1320 nsSNPs retrieved from the NCBI database, initially 16 were predicted as deleterious by 9 tools. Further assessment of their domain association, conservation profile, homology models, interatomic interaction, and Molecular Dynamic Simulation revealed that the variant I463S is likely to be the most deleterious for the structure and function of the protein. Despite the limitations of computational algorithms, our analyses have provided insights that can be a valuable resource for further in vitro and in vivo research on GRIN2A-associated diseases.

High risk genetic variants of human insulin receptor substrate 1(IRS1) infer structural instability and functional interference.

Insulin receptor substrate 1(IRS1) is a signaling adapter protein encoded by the IRS1 gene. This protein delivers signals from insulin and insulin-like growth factor-1(IGF-1) receptors to the phosphatidylinositol 3-kinases (P13K)/protein kinase B (Akt) and Extracellular signal-regulated kinases (Erk) - Mitogen-activated protein (MAP) kinase pathways, which regulate particular cellular processes. Mutations in this gene have been linked to type 2 diabetes mellitus, a heightened risk of insulin resistance, and an increased likelihood of developing a number of different malignancies. The structure and function of IRS1 could be severely compromised as a result of single nucleotide polymorphism (SNP) type genetic variants. In this study, we focused on identification of the most harmful non-synonymous SNPs (nsSNPs) of the IRS1 gene as well as prediction of their structural and functional consequences. Six different algorithms made the initial prediction that 59 of the 1142 IRS1 nsSNPs would have a negative impact on the protein structure. In-depth evaluations detected 26 nsSNPs located inside the functional domains of IRS1. Following that, 16 nsSNPs were identified as more harmful based on conservation profile, hydrophobic interaction, surface accessibility, homology modelling, and inter-atomic interactions. Following an in-depth analysis of protein stability, M249T (rs373826433), I223T (rs1939785175) and V204G (rs1574667052) were identified as three most deleterious SNPs and were subjected to molecular dynamics simulation for further insights. These findings will help us understand the implications for disease susceptibility, cancer progression, and the efficacy of therapeutic development against IRS1 gene mutants.Communicated by Ramaswamy H. Sarma.

Pharmacoinformatics and molecular dynamics simulation approach to identify anti-diarrheal potentials of Centella asiatica (L.) Urb. against Vibrio cholerae.

Vibrio cholerae, the etiological agent of cholera, causes dehydration and severe diarrhea with the production of cholera toxin. Due to the acquired antibiotic resistance, V. cholerae has drawn attention to the establishment of novel medications to counteract the virulence and viability of the pathogen. Centella asiatica is a medicinal herb native to Bangladesh that has a wide range of medicinal and ethnobotanical applications including anti-bacterial properties. In the present investigation, a total of 25 bioactive phytochemicals of C. asiatica have been screened virtually through molecular docking, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analyses, and molecular dynamics simulation. Our results revealed four lead compounds as Viridiflorol (-8.7 Kcal/mol), Luteolin (-8.1 Kcal/mol), Quercetin (-8.0 Kcal/mol) and, Geranyl acetate (-7.1 Kcal/mol) against V. cholerae Toxin co-regulated pilus virulence regulatory protein (ToxT). All the lead compounds have been found to possess favorable pharmacokinetic, pharmacodynamics, and molecular dynamics properties. Toxicity analysis revealed satisfactory results with no major side effects. Molecular dynamics simulation was performed for 100 ns that revealed noteworthy conformational stability and structural compactness for all the lead compounds, especially for Quercetin. Target class prediction unveiled enzymes in most of the cases and some experimental and investigational drugs were found as structurally similar analogs of the lead compounds. These findings could aid in the development of novel therapeutics targeting Cholera disease and we strongly recommend in vitro trials of our experimental findings.Communicated by Ramaswamy H. Sarma.

Virtual screening reveals liquiritigenin as a broad-spectrum inhibitor of SARS-CoV-2 variants of concern: an in silico study.

The SARS-CoV-2 has severely impacted the lives of people worldwide. Global concern is on the rise due to a large number of unexpected mutations in the viral genome, resulting in new variants. Nature-based bioactive phytochemicals hold great promise as inhibitors against pathogenic viruses. The current study was aimed at evaluating some bioactive antiviral phytochemicals against SARS-CoV-2 variants of concern. A total of 46 phytochemicals were screened against the pathogenic spike protein of Alpha, Beta, Delta, Gamma, and Omicron variants. In addition to molecular docking, screening for favorable pharmacokinetic and pharmacodynamic properties such as absorption, distribution, metabolism, excretion, and toxicity was undertaken. For each of the aforementioned five SARS-CoV-2 variants of concern, a 100 ns molecular dynamics simulation was run to assess the stability of the complexes between their respective spike protein receptor-binding domain and the best-selected compound. From our current investigation, the natural compound liquiritigenin turned out to be the most promising potential lead compound against almost all the variants. These findings could pave the way for the development of effective medications against SARS-CoV-2 variants. However, in vivo trials in future studies are necessary for further validation of our results.Communicated by Ramaswamy H. Sarma.

Pathogen-driven gene expression patterns lead to a novel approach to the identification of common therapeutic targets.

Developing a common medication strategy for disease control and management could be greatly beneficial. Investigating the differences between diseased and healthy states using differentially expressed genes aids in understanding disease pathophysiology and enables the exploration of protein-drug interactions. This study aimed to find the most common genes in diarrhea-causing bacteria such as Salmonella enterica serovar Typhimurium, Campylobacter jejuni, Escherichia coli, Shigella dysenteriae (CESS) to find new drugs. Thus, differential gene expression datasets of CESS were screened through computational algorithms and programming. Subsequently, hub and common genes were prioritized from the analysis of extensive protein-protein interactions. Binding predictions were performed to identify the common potential therapeutic targets of CESS. We identified a total of 827 dysregulated genes that are highly linked to CESS. Notably, no common gene interaction was found among all CESS bacteria, but we identified 3 common genes in both Salmonella-Escherichia and Escherichia-Campylobacter infections. Later, out of 73 protein complexes, molecular simulations confirmed 5 therapeutic candidates from the CESS. We have developed a new pipeline for identifying therapeutic targets for a common medication strategy against CESS. However, further wet-lab validation is needed to confirm their effectiveness.

Proteome-Based Investigation Identified Potential Drug Repurposable Small Molecules Against Monkeypox Disease.

Monkeypox Virus (MPXV), the causative agent of Monkeypox (MPX) disease, is an emerging zoonotic pathogen spreading in different endemic and non-endemic nations and creating outbreaks. MPX treatment mainly includes Cidofovir and Tecovirimat but they have several side effects and solely depending on these drugs may promote the emergence of drug-resistant variants. Hence, new drugs are required to control the spread of the disease. In this study, we explored the MPXV proteome to suggest repurposable drugs. DrugBank screening revealed drugs such as Brinzolamide, Dorzolamide, Methazolamide, Zidovudine, Gemcitabine, Hydroxyurea, Fludarabine, and Tecovirimat as controls. Structural analogs of these compounds were extracted from ChEMBL Database. After Molecular docking and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET)-based screening, we identified Zidovudine (binding affinity-5.9 kcal/mol) and a Harmala alkaloid (2S,4R)-4-(9H-Pyrido[3,4-b]indol-1-yl)-1,2,4-butanetriol (binding affinity - 6.6 kcal/mol) against L2R receptor (Thymidine Kinase). Moreover, Fludarabine (binding affinity - 6.4 kcal/mol) and 5'-Dehydroadenosine (binding affinity - 6.4 kcal/mol) can strongly interact with the I4L receptor (Ribonucleotide reductase large subunit R1). Molecular Dynamics (MD) simulations suggest all of these compounds can change the C-alpha backbone, residue mobility, compactness, and solvent accessible surface area of L2R and I4L. Our results strongly suggest that these drug repurposing small molecules are worth exploring in vivo and in vitro for clinical applications.

Exploration of Streptococcus core genome to reveal druggable targets and novel therapeutics against S. pneumoniae.

Streptococcus pneumoniae (S. pneumoniae), the major etiological agent of community-acquired pneumonia (CAP) contributes significantly to the global burden of infectious diseases which is getting resistant day by day. Nearly 30% of the S. pneumoniae genomes encode hypothetical proteins (HPs), and better understandings of these HPs in virulence and pathogenicity plausibly decipher new treatments. Some of the HPs are present across many Streptococcus species, systematic assessment of these unexplored HPs will disclose prospective drug targets. In this study, through a stringent bioinformatics analysis of the core genome and proteome of S. pneumoniae PCS8235, we identified and analyzed 28 HPs that are common in many Streptococcus species and might have a potential role in the virulence or pathogenesis of the bacteria. Functional annotations of the proteins were conducted based on the physicochemical properties, subcellular localization, virulence prediction, protein-protein interactions, and identification of essential genes, to find potentially druggable proteins among 28 HPs. The majority of the HPs are involved in bacterial transcription and translation. Besides, some of them were homologs of enzymes, binding proteins, transporters, and regulators. Protein-protein interactions revealed HP PCS8235_RS05845 made the highest interactions with other HPs and also has TRP structural motif along with virulent and pathogenic properties indicating it has critical cellular functions and might go under unconventional protein secretions. The second highest interacting protein HP PCS8235_RS02595 interacts with the Regulator of chromosomal segregation (RocS) which participates in chromosome segregation and nucleoid protection in S. pneumoniae. In this interacting network, 54% of protein members have virulent properties and 40% contain pathogenic properties. Among them, most of these proteins circulate in the cytoplasmic area and have hydrophilic properties. Finally, molecular docking and dynamics simulation demonstrated that the antimalarial drug Artenimol can act as a drug repurposing candidate against HP PCS8235_RS 04650 of S. pneumoniae. Hence, the present study could aid in drugs against S. pneumoniae.

A comprehensive in silico investigation into the nsSNPs of Drd2 gene predicts significant functional consequences in dopamine signaling and pharmacotherapy.

DRD2 is a neuronal cell surface protein involved in brain development and function. Variations in the Drd2 gene have clinical significance since DRD2 is a pharmacotherapeutic target for treating psychiatric disorders like ADHD and schizophrenia. Despite numerous studies on the disease association of single nucleotide polymorphisms (SNPs) in the intronic regions, investigation into the coding regions is surprisingly limited. In this study, we aimed at identifying potential functionally and pharmaco-therapeutically deleterious non-synonymous SNPs of Drd2. A wide array of bioinformatics tools was used to evaluate the impact of nsSNPs on protein structure and functionality. Out of 260 nsSNPs retrieved from the dbSNP database, initially 9 were predicted as deleterious by 15 tools. Upon further assessment of their domain association, conservation profile, homology models and inter-atomic interaction, the mutant F389V was considered as the most impactful. In-depth analysis of F389V through Molecular Docking and Dynamics Simulation revealed a decline in affinity for its native agonist dopamine and an increase in affinity for the antipsychotic drug risperidone. Remarkable alterations in binding interactions and stability of the protein-ligand complex in simulated physiological conditions were also noted. These findings will improve our understanding of the consequence of nsSNPs in disease-susceptibility and therapeutic efficacy.

Wave-wise comparative genomic study for revealing the complete scenario and dynamic nature of COVID-19 pandemic in Bangladesh.

As the COVID-19 pandemic continues to ravage across the globe and take millions of lives and like many parts of the world, the second wave of the pandemic hit Bangladesh, this study aimed at understanding its causative agent, SARS-CoV-2 at the genomic and proteomic level and provide precious insights about the pathogenesis, evolution, strengths and weaknesses of the virus. As of Mid-June 2021, over 1500 SARS-CoV-2 genomesequences have been deposited in the GISAID database from Bangladesh which were extracted and categorized into two waves. By analyzing these genome sequences, it was discovered that the wave-2 samples had a significantly greater average rate of mutation/sample (30.79%) than the wave-1 samples (12.32%). Wave-2 samples also had a higher frequency of deletion, and transversion events. During the first wave, the GR clade was the most predominant but it was replaced by the GH clade in the latter wave. The B.1.1.25 variant showed the highest frequency in wave-1 while in case of wave-2, the B.1.351.3 variant, was the most common one. A notable presence of the delta variant, which is currently at the center of concern, was also observed. Comparison of the Spike protein found in the reference and the 3 most common lineages found in Bangladesh namely, B.1.1.7, B.1.351, B.1.617 in terms of their ability to form stable complexes with ACE2 receptor revealed that B.1.617 had the potential to be more transmissible than others. Importantly, no indigenous variants have been detected so far which implies that the successful prevention of import of foreign variants can diminish the outbreak in the country.

Genomic Surveillance of SARS-CoV-2 Viruses Collected during the Ending Phase of the First Wave of the COVID-19 Pandemic in Bangladesh.

Mutations, deletions, and the emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may pose a serious health threat. Here, we report the genome sequences of SARS-CoV-2 viruses that were collected from SARS-CoV-2-infected patients during the end phase of the first wave of the COVID-19 pandemic in Dhaka, Bangladesh.

Novel mutations in NSP-1 and PLPro of SARS-CoV-2 NIB-1 genome mount for effective therapeutics.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), is rapidly acquiring new mutations. Analysis of these mutations is necessary for gaining knowledge regarding different aspects of therapeutic development. Previously, we have reported a Sanger method-based genome sequence of a viral isolate named SARS-CoV-2 NIB-1, circulating in Bangladesh. The genome has four novel non-synonymous mutations in V121D, V843F, A889V, and G1691C positions. RESULTS: Using different computational tools, we have found V121D substitution has the potential to destabilize the non-structural protein-1 (NSP-1). NSP-1 inactivates the type-1 interferon-induced antiviral system. Hence, this mutant could be a basis of attenuated vaccines against SARS-CoV-2. V843F, A889V, and G1691C are all located in nonstructural protein-3 (NSP-3). G1691C can decrease the flexibility of the protein. V843F and A889V might change the binding pattern and efficacy of SARS-CoV-2 papain-like protease (PLPro) inhibitor GRL0617. V843F substitution in PLPro was the most prevalent mutation in the clinical samples. This mutation showed a reduced affinity for interferon-stimulated gene-15 protein (ISG-15) and might have an impact on innate immunity and viral spread. However, V843F+A889V double mutant exhibited the same binding affinity as wild type PLPro. A possible reason behind this phenomenon can be that V843F is a conserved residue of PLPro which damaged the protease structure, but A889V, a less conserved residue, presumably neutralized that damage. CONCLUSIONS: Mutants of NSP-1 could provide attenuated vaccines against coronavirus. Also, these mutations of PLPro might be targeted to develop better anti-SARS therapeutics. We hope our study will help to get better insides during the development of attenuated vaccine and PLPro inhibitors.

Whole genome sequencing for revealing the point mutations of SARS-CoV-2 genome in Bangladeshi isolates and their structural effects on viral proteins.

Coronavirus disease-19 (COVID-19) caused by SARS-CoV-2 has already killed more than one million people worldwide. Since novel coronavirus is a new virus, mining its genome sequence is of crucial importance for drug/vaccine(s) development. Whole genome sequencing is a helpful tool in identifying genetic changes that occur in a virus when it spreads through the population. In this study, we performed complete genome sequencing of SARS-CoV-2 to unveil the genomic variation and indel, if present. We discovered thirteen (13) mutations in Orf1ab, S and N gene where seven (7) of them turned out to be novel mutations from our sequenced isolate. Besides, we found one (1) insertion and seven (7) deletions from the indel analysis among the 323 Bangladeshi isolates. However, the indel did not show any effect on proteins. Our energy minimization analysis showed both stabilizing and destabilizing impact on viral proteins depending on the mutation. Interestingly, all the variants were located in the binding site of the proteins. Furthermore, drug binding analysis revealed marked difference in interacting residues in mutants when compared to the wild type. Our analysis also suggested that eleven (11) mutations could exert damaging effects on their corresponding protein structures.

A comprehensive review of tumor proliferative and suppressive role of semaphorins and therapeutic approaches.

Semaphorins have been traditionally known as axon guidance proteins that negatively regulate axonal growth. However, in the past couple of decades, their versatile role in so many other biological processes has come to prominence as well. One such example is their role in cancer. In this review article, the focus was on the tumor proliferative and tumor suppressive role of all 20 semaphorin family members under the 7 semaphorin classes found in vertebrates and invertebrates as well as the ongoing and emerging therapeutic approaches to combat semaphorin-mediated cancers. Except sema6C, 19 of the 20 non-viral semaphorin family members have been discovered to be associated with cancer in one way or another. Eleven semaphorin family members have been discovered to be tumor proliferative and 8 to be tumor suppressive. Six therapeutic avenues and their safety profiles have been discussed which are currently at use or at the various stages of development. Finally, perspectives on which approach is the best for treating cancers associated with semaphorins have been given.

Designing a novel mRNA vaccine against SARS-CoV-2: An immunoinformatics approach.

SARS-CoV-2 is the deadly virus behind COVID-19, the disease that went on to ravage the world and caused the biggest pandemic 21st century has witnessed so far. On the face of ongoing death and destruction, the urgent need for the discovery of a vaccine against the virus is paramount. This study resorted to the emerging discipline of immunoinformatics in order to design a multi-epitope mRNA vaccine against the spike glycoprotein of SARS-CoV-2. Various immunoinformatics tools were utilized to predict T and B lymphocyte epitopes. The epitopes were channeled through a filtering pipeline comprised of antigenicity, toxicity, allergenicity, and cytokine inducibility evaluation with the goal of selecting epitopes capable of generating both T and B cell-mediated immune responses. Molecular docking simulation between the epitopes and their corresponding MHC molecules was carried out. 13 epitopes, a highly immunogenic adjuvant, elements for proper sub-cellular trafficking, a secretion booster, and appropriate linkers were combined for constructing the vaccine. The vaccine was found to be antigenic, almost neutral at physiological pH, non-toxic, non-allergenic, capable of generating a robust immune response and had a decent worldwide population coverage. Based on these parameters, this design can be considered a promising choice for a vaccine against SARS-CoV-2.