Molecular docking, pharmacokinetic prediction and molecular dynamics simulations of tankyrase inhibitor compounds with the protein glucokinase, induced in the development of diabetes.

GCK is a protein that plays a crucial role in the sensing and regulation of glucose homeostasis, which associates it with disorders of carbohydrate metabolism and the development of several pathologies, including gestational diabetes. This makes GCK an important therapeutic target that has aroused the interest of researchers to discover GKA that are simultaneously effective in the long term and free of side effects. TNKS is a protein that interacts directly with GCK; recent studies have shown that it inhibits GCK action, which affects glucose detection and insulin secretion. This justifies our choice of TNKS inhibitors as ligands to test their effects on the GCK-TNKS complex. For this purpose, we investigated the interaction of the GCK-TNKS complex with 13 compounds (TNKS inhibitors and their analogues) using the molecular docking approach as a first step, after which the compounds that generated the best affinity scores were evaluated for drug similarity and pharmacokinetic properties. Subsequently, we selected the six compounds that generated high affinity and that were in accordance with the parameters of the drug rules as well as pharmacokinetic properties to ensure a molecular dynamics study. The results allowed us to favor the two compounds (XAV939 and IWR-1), knowing that even the tested compounds (TNKS 22, (2215914) and (46824343)) produced good results that can also be exploited. These results are therefore interesting and encouraging, and they can be exploited experimentally to discover a treatment for diabetes, including gestational diabetes.Communicated by Ramaswamy H. Sarma.

Association between nutritional status, body composition, and fitness level of adolescents in physical education in Casablanca, Morocco.

Aim: This study aims to analyze and compare dietary intake, as well as to examine the associations between energy intake in terms of macronutrients, body composition, and physical fitness (PF) specifically cardiorespiratory endurance (CE) among a sample of young adolescents aged 15 to 18 years, who participate in physical education and sports sessions in public schools in Casablanca, Morocco. Materials and methods: A total of 311 participants, including 156 girls and 154 boys, were included in the study. Each participant maintained a food diary for 3 days during the same study week. Additionally, body composition measurements were taken using bioelectrical impedance analysis (BIA). The PF was assessed using the validated mini-Cooper test (6 min). Results: The results show that the participants had an average total energy intake of 2386.7 ± 492.7 kcal. A significant difference was observed between boys and girls, with average energy intakes of 2468.8 ± 531.1 kcal and 2304.0 ± 437.0 kcal, respectively. These dietary intakes were significantly lower than their needs and nutritional recommendations. The associations of nutritional status, sex, body mass index (BMI) and physical fitness (PF) were tested and a positive correlation was observed following an adequate intake of carbohydrates (CHO) and proteins on Vo2max, while a negative association was observed with regard to Body fat for both sexes. Boys exhibit significantly better PF than girls (p < 0.01). Obese participants had the lowest PF and an unbalanced nutritional status, the adolescents with a normal weight p < 0.01 displayed a high level of PF compared to individuals in other weight categories. Conclusion: The PF is significantly associated with macronutrient intake status and body composition, especially BMI and BF. The Underweight, overweight, and obese students demonstrated poorer performance in physical fitness indices compared to normal-weight. Adolescents adhering to recommended CHO and protein intake levels tend to exhibit enhanced physical fitness. Implementing strategies to encourage students to maintain a balanced diet and engage in regular physical exercise is essential.

Computational analysis of missense variants of human MC4R and childhood obesity.

Industrialized and developing nations face severe public health problems related to childhood obesity. Previous studies revealed that the melanocortin-4 receptor gene (MC4R) is the most prevalent monogenic cause of severe early obesity. Due to its influence on food intake and energy expenditure via neuronal melanocortin-4 receptor pathways, MC4R is recognized as a regulator of energy homeostasis. This study used a variety of computational systems to analyze 273 missense variations of MC4R in silico. Several tools, including PolyPhen, PROVEAN, SIFT, SNAP2, MutPred2, PROVEAN, SNP&GO and Mu-Pro, I-Mutant, PhD-SNP, SAAFEC-SEQ I-Mutant, and ConSurf, were used to make predictions of 13 extremely confident nsSNPs that are harmful and disease-causing (E308k, P299L, D298H, C271F, C271R, P260L, T246N, G243R, C196Y, W174C, Y157S, D126Y, and D90G). The results of our study suggest that these MC4R nsSNPs may disrupt normal protein function, leading to an increased risk of childhood obesity. These results highlight the potential use of these nsSNPs as biomarkers to predict susceptibility to obesity and as targets for personalized interventions.

Molecular docking analysis of PPARγ with phytochemicals from Moroccan medicinal plants.

PPARγ agonists play a crucial role in regulating metabolic homeostasis for treating type-2 diabetes (T2D). Due to the adverse side effects associated with thiazolidinediones, a class of PPARγ agonists, there is a growing interest in identifying natural compounds from medicinal plants that have the potential to bind PPARγ. In this study, we extensively investigated Moroccan phytochemicals using computational structure-based screening with the crystal structure of the PPARγ ligand-binding domain (PDB ID: 7awc) to discover novel phytochemicals targeting PPARγ. The docking results of 540 Moroccan phytochemicals were integrated into online databases for further exploitation through in-depth studies. Drug-likeness analysis was performed to assess the phytochemicals drug-like properties. Two promising phytochemicals, 3,4-dicaffeoylquinic acid and Chlorogenic acid, were identified, both exhibiting high docking affinity and unique binding site interactions compared to the established PPARγ full agonist, rosiglitazone. Molecular dynamics simulations of 100 ns were conducted to examine the stability of the complexes formed by both compounds within the PPARγ active site, and their dynamic behavior was compared to the reference structure of PPARγ alone and with rosiglitazone. Binding free energy calculations demonstrated that 3,4-dicaffeoylquinic acid and Chlorogenic acid exhibited higher binding free energy than the reference agonist, suggesting their potential as candidates for experimental validation in future drug discovery efforts targeting PPARγ for the treatment of T2D and metabolic syndrome.

Identification of Zika virus NS2B-NS3 protease and NS5 polymerase inhibitors by structure-based virtual screening of FDA-approved drugs.

Zika virus (ZIKV) is a mosquito-borne human flavivirus responsible that causing emergency outbreaks in Brazil. ZIKV is suspected of causing Guillain-Barre syndrome in adults and microcephaly. The NS2B-NS3 protease and NS5 RNA-dependent RNA polymerase (RdRp), central to ZIKV multiplication, have been identified as attractive molecular targets for drugs. We performed a structure-based virtual screening of 2,659 FDA-approved small molecule drugs in the DrugBank database using AutoDock Vina in PyRx v0.8. Accordingly, 15 potential drugs were selected as ZIKV inhibitors because of their high values (binding affinity - binding energy) and we analyzed the molecular interactions between the active site amino acids and the compounds. Among these drugs, tamsulosin was found to interact most efficiently with NS2B/NS3 protease, as indicated by the lowest binding energy value (-8.27 kJ/mol), the highest binding affinity (-5.7 Kcal/mol), and formed H-bonds with amino acid residues TYRB130, SERB135, TYRB150. Furthermore, biotin was found to interact most efficiently with NS5 RdRp with a binding energy of -150.624 kJ/mol, a binding affinity of -5.6 Kcal/mol, and formed H-bonds with the amino acid residues ASPA665 and ASPA540. In vitro, in vivo, and clinical studies are needed to demonstrate anti-ZIKV safety and the efficacy of these FDA-approved drug candidates.Communicated by Ramaswamy H. Sarma.

Identification of novel T-cell epitopes on monkeypox virus and development of multi-epitopes vaccine using immunoinformatics approaches.

Monkeypox virus (MPV) is closely related to the smallpox virus, and previous data from Africa suggest that the smallpox vaccine (VARV) is at least 85% effective in preventing MPV. No multi-epitope vaccine has yet been developed to prevent MPV infection. In this work, we used in silico structural biology and advanced immunoinformatic strategies to design a multi-epitope subunit vaccine against MPV infection. The designed vaccine sequence is adjuvanted with CpG-ODN and includes HTL/CTL epitopes for similar proteins between vaccinia virus (VACV) that induced T-cell production in vaccinated volunteers and the first draft sequence of the MPV genome associated with the suspected outbreak in several countries, May 2022. In addition, the specific binding of the modified vaccine and the immune Toll-like receptor 9 (TLR9) was estimated by molecular interaction studies. Strong interaction in the binding groove as well as good docking scores confirmed the stringency of the modified vaccine. The stability of the interaction was confirmed by a classical molecular dynamics simulation and normal mode analysis. Then, the immune simulation also indicated the ability of this vaccine to induce an effective immune response against MPV. Codon optimization and in silico cloning of the vaccine into the pET-28a (+) vector also showed its expression potential in the E. coli K12 system. The promising data obtained from the various in silico studies indicate that this vaccine is effective against MPV. However, additional in vitro and in vivo studies are still needed to confirm its efficacy.Communicated by Ramaswamy H. Sarma.

Computational analysis of structural and functional evaluation of the deleterious missense variants in the human CTLA4 gene.

CTLA-4 is an immune checkpoint receptor that negatively regulates the T-cell function expressed after T-cell activation to break the immune response. The current study predicted the genomic analysis to explore the functional variations of missense SNPs in the human CTLA4 gene using PolyPhen2, SIFT, PANTHER, PROVEAN, Fathmm, Mutation Assessor, PhD-SNP, SNPs&GO, SNAP2, and MutPred2. Phylogenetic conservation protein was predicted by ConSurf. Protein structural analysis was carried out by I-Mutant3, MUpro, iStable2, PremPS, and ERIS servers. Molecular dynamics trajectory analysis (RMSD, RMSF, Rg, SASA, H-bonds, and PCA) was performed to analyze the dynamic behavior of native and mutant CTLA-4 at the atomic level. Our in-silico analysis suggested that C58S, G118R, P137Q, P137R, P137L, P138T, and G146L variants were predicted to be the most deleterious missense variants and highly conserved residues. Moreover, the molecular dynamics analysis proposed a decrease in the protein stability and compactness with the P137R and P138T highlighting the impact of these variants on the function of the CTLA-4 protein.Communicated by Ramaswamy H. Sarma.

MBL2 gene polymorphisms related to HIV-1 infection susceptibility and treatment response.

Human Mannose-binding lectin (MBL) is a protein encoded by MBL2 gene involved in the activation of the lectin-complement pathway. Several studies emphasized the role of MBL2 gene in several infectious diseases' susceptibility, including HIV-1 infection. We aim to investigate the impact of 10 MBL2 gene polymorphisms located in the promoter, 5'UTR and exon 1 regions on HIV-1 physiopathology. The polymorphisms genotyping of 400 individuals, which 200 were HIV-1 positive patients and 200 were controls, was performed by PCR-sequencing. Our results showed that rs503037 and rs1800451 polymorphisms are associated with a high risk of HIV-1 infection susceptibility while rs7096206 and rs11003123 showed a protective effect. A significant association between haplotype CGA and HIV-1 infection susceptibility was also found in the exon 1 region. Moreover, rs11003124, rs7084554, rs36014597 and rs11003123 polymorphisms revealed an association with treatment response outcome as measured by RNA viral load. This study highlights the importance of MBL2 polymorphisms in the modulation of HIV-1 infection susceptibility and the contribution to treatment response outcomes among Moroccan subjects.

Design of a multi-epitope Zika virus vaccine candidate - an in-silico study.

Zika virus (ZIKV), an RNA virus, rapidly spreads Aedes mosquito-borne sickness. Currently, there are neither effective vaccines nor therapeutics available to prevent or treat ZIKV infection. In this study, to address these unmet medical needs, we aimed to design B- and T-cell candidate multi-epitope-based subunit against ZIKV using an in silico approach. In this study we applied immunoinformatics, molecular docking, and dynamic simulation assessments targeting the most immunogenic proteins; the capsid (C), envelope (E) proteins and the non-stuctural protein (NS1), described in our previous study, and which predicted immunodominant B and T cell epitopes. The final non-allergenic and highly antigenic multi-epitope was constituted of immunogenic screened-epitopes (3 CTL and 3 HTL) and the ß-defensin as an adjuvant that have been linked using EAAAK, AAY, and GPGPG linkers, respectively. The final construct containing 143 amino acids was characterized for its allergenicity, antigenicity, and physiochemical properties; and found to be safe and immunogenic with a good prediction of solubility. The existence of IFN-γ epitopes asserts the capacity to trigger strong immune responses. Subsequently, the molecular docking among vaccine and immune receptors (TLR2/TLR4) was revealed with a good binding affinity with and stable molecular interactions. Molecular dynamics simulation confirmed the stability of the complexes. Finally, the construct was subjected to in silico cloning demonstrating the efficiently of its expression in E.coli. However, this study needs the experimental validation to demonstrate vaccine safety and efficacy.Communicated by Ramaswamy H. Sarma.

Reverse vaccinology-based prediction of a multi-epitope SARS-CoV-2 vaccine and its tailoring to new coronavirus variants.

The genome feature of SARS-CoV-2 leads the virus to mutate and creates new variants of concern. Tackling viral mutations is also an important challenge for the development of a new vaccine. Accordingly, in the present study, we undertook to identify B- and T-cell epitopes with immunogenic potential for eliciting responses to SARS-CoV-2, using computational approaches and its tailoring to coronavirus variants. A total of 47 novel epitopes were identified as immunogenic triggering immune responses and no toxic after investigation with in silico tools. Furthermore, we found these peptide vaccine candidates showed a significant binding affinity for MHC I and MHC II alleles in molecular docking investigations. We consider them to be promising targets for developing peptide-based vaccines against SARS-CoV-2. Subsequently, we designed two efficient multi-epitopes vaccines against the SARS-CoV-2, the first one based on potent MHC class I and class II T-cell epitopes of S (FPNITNLCPF-NYNYLYRLFR-MFVFLVLLPLVSSQC), M (MWLSYFIASF-GLMWLSYFIASFRLF), E (LTALRLCAY-LLFLAFVVFLLVTLA), and N (SPRWYFYYL-AQFAPSASAFFGMSR). The second candidate is the result of the tailoring of the first designed vaccine according to three classes of SARS-CoV-2 variants. Molecular docking showed that the protein-protein binding interactions between the vaccines construct and TLR2-TLR4 immune receptors are stable complexes. These findings confirmed that the final multi-epitope vaccine could be easily adapted to new viral variants. Our study offers a shortlist of promising epitopes that can accelerate the development of an effective and safe vaccine against the virus and its adaptation to new variants.Communicated by Ramaswamy H. Sarma.

Association between Methylene-Tetrahydrofolate Reductase C677T Polymorphism and Human Immunodeficiency Virus Type 1 Infection in Morocco.

Human immunodeficiency virus type 1 (HIV-1) infection varies substantially among individuals. One of the factors influencing viral infection is genetic variability. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is a genetic factor that has been correlated with different types of pathologies, including HIV-1. The MTHFR gene encodes the MTHFR enzyme, an essential factor in the folate metabolic pathway and in maintaining circulating folate and methionine at constant levels, thus preventing the homocysteine accumulation. Several studies have shown the role of folate on CD4+ T lymphocyte count among HIV-1 subjects. In this case-control study we aimed to determine the association between the MTHFR C677T polymorphism and HIV-1 infection susceptibility, AIDS development, and therapeutic outcome among Moroccans. The C677T polymorphism was genotyped by polymerase chain reaction followed by fragment length polymorphism digestion in 214 participants living with HIV-1 and 318 healthy controls. The results of the study revealed no statistically significant association between MTHFR C677T polymorphism and HIV-1 infection (P > .05). After dividing HIV-1 subjects according to their AIDS status, no significant difference was observed between C677T polymorphism and AIDS development (P > .05). Furthermore, regarding the treatment response outcome, as measured by HIV-1 RNA viral load and CD4+ T cell counts, no statistically significant association was found with MTHFR C677T polymorphism. We conclude that, in the genetic context of the Moroccan population, MTHFR C677T polymorphism does not affect HIV-1 infection susceptibility, AIDS development, or response to treatment. However, more studies should be done to investigate both genetic and nutritional aspects for more conclusive results.

Data insights from a Moroccan phytochemical database (MPDB) derived from aromatic & medicinal plants.

The geographical location of Morocco and the diversity of its topography ensure a high variability of climate conditions, ranging from humid to Saharan, and extending through subhumid, arid, and semi-arid stages. This variability offers a high floristic diversity, while the medical use of these phytochemicals has not been fully explored. Advanced computer-aided drug discovery utilizes chemical biology to accelerate the study of phytochemicals at the molecular level and discover novel therapeutic pathways. Currently, there is no online resource for phytochemicals in Morocco. Therefore, it is of interest to describe the Moroccan Phytochemicals Database (MPDB), accessible, featuring over 600 phytochemicals derived from journal articles and other reports. The web interface of the database, which is simple and easy to use, provides each phytochemical's reference, plant sources, 3D structures, and all related information. Furthermore, we provide direct links to commercially available analogs from Mcule. In addition, we provide the results of the first virtual screening against cardiovascular targets. We present these data to facilitate further exploration and exploitation of Morocco's rich phytochemical resources, and to contribute to the global understanding and application of these compounds in the medical and scientific communities.

The EPIYA-ABCC motif of Helicobacter pylori cagA gene and gastric carcinogenesis in Casablanca population.

Background: H. pylori infection induce atrophic gastritis (AG) and intestinal metaplasia (IM) that can lead to gastric cancer (GC). The severity of gastric lesions is related to H. pylori genetic diversity. The oncogenic potential of H. pylori cagA virulence factor is linked to its high polymorphic EPIYA motifs. Objectives: Our aim was to evaluate the association of EPIYA motifs with the risk of AG and IM in Casablanca population. Methods: A total of 210 patients suffering from gastric lesions (chronic gastritis, AG, and IM) was enrolled. H. pylori infection and the type of lesions were diagnosed by ureC PCR and histological examination, respectively. Detection of the cagA gene, and the type of EPIYA motifs, were carried out by PCR. Results: The prevalence of H. pylori and cagA gene was 95% and 37%, respectively. CagA-positive strains were associated with the risk of IM. The EPIYA motifs detected were: EPIYA-ABC (58%), EPIYA-ABCC (22%), and EPIYA-AB (20%). The EPIYA-ABCC motif was associated with the risk of IM (p-value = 0.007), compared to AG (p-value = 0.28). Conclusion: The EPIYA-ABCC motif might be a useful marker for the identification of patients at high risk of developing IM that can lead to GC.

Computational Analysis of Missense Variants in the Human Transmembrane Protease Serine 2 (TMPRSS2) and SARS-CoV-2.

The human transmembrane protease serine 2 (TMPRSS2) protein plays an important role in prostate cancer progression. It also facilitates viral entry into target cells by proteolytically cleaving and activating the S protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the current study, we used different available tools like SIFT, PolyPhen2.0, PROVEAN, SNAP2, PMut, MutPred2, I-Mutant Suite, MUpro, iStable, ConSurf, ModPred, SwissModel, PROCHECK, Verify3D, and TM-align to identify the most deleterious variants and to explore possible effects on the TMPRSS2 stability, structure, and function. The six missense variants tested were evaluated to have deleterious effects on the protein by SIFT, PolyPhen2.0, PROVEAN, SNAP2, and PMut. Additionally, V160M, G181R, R240C, P335L, G432A, and D435Y variants showed a decrease in stability by at least 2 servers; G181R, G432A, and D435Y are highly conserved and identified posttranslational modifications sites (PTMs) for proteolytic cleavage and ADP-ribosylation using ConSurf and ModPred servers. The 3D structure of TMPRSS2 native and mutants was generated using 7 meq as a template from the SwissModeller group, refined by ModRefiner, and validated using the Ramachandran plot. Hence, this paper can be advantageous to understand the association between these missense variants rs12329760, rs781089181, rs762108701, rs1185182900, rs570454392, and rs867186402 and susceptibility to SARS-CoV-2.

Association of Helicobacter pylori vacA polymorphisms with the risk of gastric precancerous lesions in a Moroccan population.

INTRODUCTION: Helicobacter pylori infection is the major risk factor of atrophic gastritis and intestinal metaplasia. The vacA gene is one of the most virulence factors of H. pylori and genetic diversity in its s, m, i, and d regions is associated with gastric lesions severity. This study aimed to investigate the association of vacA s, m, i, and d regions with the risk of atrophic gastritis and intestinal metaplasia in a Casablanca population. METHODOLOGY: A total of 210 patients suffering from gastric lesions (chronic gastritis, atrophic gastritis, and intestinal metaplasia) were enrolled. The type of lesion was diagnosed by histological examination. Detection of H. pylori infection and genotyping of vacA regions were carried out by PCR. RESULTS: The prevalence of H. pylori was 95%. The most common vacA genotypes were s2 (51.5%), m2 (77%), i2 (60.5%), and d2 (58.5%). VacA s1, m1, and i1 genotypes were associated with a high risk of intestinal metaplasia, while the vacA d1 genotype increases the risk of atrophic gastritis and intestinal metaplasia. The most common vacA combination was s2/m2/i2/d2 (52%), and it was more detected in chronic gastritis. The moderate virulent vacA combination (s1/m2/i1/d1) increases the risk of atrophic gastritis, while the most virulent vacA combination (s1/m1/i1/d1) increases the risk of intestinal metaplasia. CONCLUSIONS: Genotyping of vacA d region might be a reliable marker for the identification of vacA virulent strains that represent a high risk of developing precancerous lesions (atrophic gastritis and intestinal metaplasia).

Programmed cell death-1 single-nucleotide polymorphism rs10204525 is associated with human immunodeficiency virus type 1 RNA viral load in HIV-1-infected Moroccan subjects.

Human Immunodeficiency Virus (HIV-1) infections are characterized by dysfunctional cellular and humoral antiviral immune responses. The progressive loss of effector functions in chronic viral infection has been associated with the up-regulation of programmed death-1 (PD-1), a negative regulator of activated T cells and Natural Killer cells. In HIV-1 infection, increased levels of PD-1 expression correlate with CD8 + T-cell exhaustion. In vitro, PD-1 blockade using PD-1 antibodies led to an increase in HIV-1 specific CD8 + T and memory B cell proliferation. We aimed to investigate the impact of PDCD1 rs10204525 polymorphism on HIV-1 susceptibility, AIDS development, and treatment response outcomes in HIV-1 infection in a Moroccan population. A total of 214 HIV-1 seropositive and 250 seronegative subjects were enrolled to investigate the association between the between the single-nucleotide polymorphism (SNP) rs10204525 of PDCD1 gene and HIV-1 pathogenesis using a predesigned TaqMan SNP genotyping assay. No significant association was found between rs10204525 and susceptibility to HIV-1 infection and AIDS development (p > 0.05). Genotype frequencies were significantly associated with the viral load before ART (p = 0.0105). HIV-1 viral load was significantly higher among subjects with the CC compared to TT genotype (p = 0.0043). In treated subjects, the median of viral load levels was significantly higher in CC and CT groups than TT subjects (p < 0.005). However, analysis of the correlation between CD4 + T-cell levels and PDCD1 polymorphism before and after ART showed no significant difference (p > 0.05). Our results demonstrated that rs10204525 polymorphism does not affect HIV-1 infection. However, this polymorphism may affect the response to treatment as measured by RNA viral load levels.

In Silico Analysis of High-Risk Missense Variants in Human ACE2 Gene and Susceptibility to SARS-CoV-2 Infection.

SARS-CoV-2 coronavirus uses for entry to human host cells a SARS-CoV receptor of the angiotensin-converting enzyme (ACE2) that catalyzes the conversion of angiotensin II into angiotensin (1-7). To understand the effect of ACE2 missense variants on protein structure, stability, and function, various bioinformatics tools were used including SIFT, PANTHER, PROVEAN, PolyPhen2.0, I. Mutant Suite, MUpro, SWISS-MODEL, Project HOPE, ModPred, QMEAN, ConSurf, and STRING. All twelve ACE2 nsSNPs were analyzed. Six ACE2 high-risk pathogenic nsSNPs (D427Y, R514G, R708W, R710C, R716C, and R768W) were found to be the most damaging by at least six software tools (cumulative score between 6 and 7) and exert deleterious effect on the ACE2 protein structure and likely function. Additionally, they revealed high conservation, less stability, and having a role in posttranslation modifications such a proteolytic cleavage or ADP-ribosylation. This in silico analysis provides information about functional nucleotide variants that have an impact on the ACE2 protein structure and function and therefore susceptibility to SARS-CoV-2.

Immuno-informatics-based Identification of Novel Potential B Cell and T Cell Epitopes to Fight Zika Virus Infections.

BACKGROUND: Globally, the recent outbreak of Zika virus (ZIKV) in Brazil, Asia Pacific, and other countries highlighted the unmet medical needs. Currently, there are neither effective vaccines nor therapeutics available to prevent or treat ZIKV infection. OBJECTIVE: In this study, we aimed to design an epitope-based vaccine for ZIKV using an in silico approach to predict and analyze B- and T-cell epitopes. METHODS: The prediction of the most antigenic epitopes has targeted the capsid and envelope proteins as well as non-structural proteins NS5 and NS3 using immune-informatics tools PROTPARAM, CFSSP, PSIPRED, and Vaxijen v2.0. B and T-cell epitopes were predicted using ABCpred, IEDB, TepiTool, and their toxicity was evaluated using ToxinPred. The 3-dimensional epitope structures were generated by PEP-FOLD. Energy minimization was performed using Swiss- Pdb Viewer, and molecular docking was conducted using PatchDock and FireDock server. RESULTS: As a result, we predicted 307 epitopes of MHCI (major histocompatibility complex class I) and 102 epitopes of MHCII (major histocompatibility complex class II). Based on immunogenicity and antigenicity scores, we identified the four most antigenic MHC I epitopes: MVLAILAFLR (HLA-A*68:01), ETLHGTVTV (HLA-A*68:02), DENHPYRTW (HLA-B*44:02), QEGVFH TMW (HLA-B*44:03) and TASGRVIEEW (HLA-B*58:01), and MHC II epitopes: IIKKFKKDLAAMLRI (HLA-DRB3*02:02), ENSKMMLELDPPFGD (HLA-DRB3*01:01), HAET WFFDENHPYRT (HLA-DRB3*01:01), TDGVYRVMTRRLLGS (HLA-DRB1*11:01), and DGCW YGMEIRPRKEP (HLA-DRB5*01:01). CONCLUSION: This study provides novel potential B cell and T cell epitopes to fight against Zika virus infections and may prompt further development of vaccines against ZIKV and other emerging infectious diseases. However, further investigations for protective immune response by in vitro and in vivo studies to ratify immunogenicity, the safety of the predicted structure, and ultimately for the vaccine properties to prevent ZIKV infections are warranted.

Structure-guided discovery approach identifies potential lead compounds targeting Mpro of SARS-CoV-2.

The ongoing coronavirus disease 19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become fatal for the world with affected population crossing over 25 million in more than 217 countries, consequently declared a global pandemic by the World Health Organization. Unfortunately, neither specific prophylactic or therapeutic drugs nor vaccines are available. To address the unmet medical needs, we explored a strategy identifying new compounds targeting the main protease (Mpro) of SARS-CoV-2. Targeting the SARS-CoV-2 Mpro crystal structure (PDB ID: 6LU7) a combination of in silico screening, molecular docking, and dynamic approaches, a set of 5000 compounds of the ZINC database were screened. As a result, we identified and ranked the top 20 compounds based on the scores of ligand-interaction, their drug-likeness properties, and their predicted antiviral efficacies. The prominent drug-like and potent inhibitory compounds are 2-[2-(2-aminoacetyl) aminoacetyl] amino-3-(4-hydroxyphenyl)-propanamide (ZINC000004762511), 6'-fluoroaristeromycin (ZINC000001483267) and cyclo (L-histidyl-L-histidyl) (ZINC000005116916) scaffolds. Further in vitro and in vivo validations are required to demonstrate anti-SARS-CoV-2 activities.

Association of Tumor Necrosis Factor Receptor 1 Promoter Gene Polymorphisms (-580 A/G and -609 G/T) and TNFR1 Serum Levels with the Susceptibility to Gastric Precancerous Lesions and Gastric Cancer Related to H. pylori Infection in a Moroccan Population.

Chronic inflammation due to H. pylori infection is the risk factor of gastric cancer (GC). Through its receptor (TNFR1), TNF-α plays a fundamental role in inflammatory, infectious, and tumor processes. Dysregulation of TNFR1 gene expression could impact many biological processes that can lead to cancer. This study is aimed at evaluating the association of TNFR1 promoter gene polymorphisms (-580 A/G and -609 G/T) and TNFR1 serum levels with GC and precancerous lesion susceptibility. Patients suffering from gastric lesions (65 chronic gastritis, 50 precancerous lesions, and 40 GC) related to H. pylori infection and 63 healthy controls (HC) were involved in this study. Individuals are genotyped by TNFR1 gene promoter sequencing, and TNFR1 serum levels were measured by the ELISA quantitative method. Concerning TNFR1 -609 G/T locus, we noticed that the T allele was associated with an attenuated susceptibility to GC (OR = 0.4; p value = 0.02). At the genotypic level and under the recessive model, the TNFR1 -609 TT genotype showed a decreased risk of GC (OR = 0.3, p value = 0.03) compared to the combined (GG/GT) genotypes. TNFR1 serum levels have been increased together with gastric lesion severity (p value < 0.05). The TNFR1 -609 TT genotype seemed linked to a low level of sTNFR1 compared to GT and GG genotypes (p value = 0.07). Concerning TNFR1 -580 A/G locus, no significant relation was noticed between this polymorphism and GC susceptibility, as well as with the TNFR1 serum level. Our results suggest that the TNFR1 -609 T allele appears to have a protective effect against GC. High levels of TNFR1 serum levels seemed to be associated with the aggressiveness of gastric lesions. Therefore, our results suggest that TNFR1 -609 T/G polymorphism and the TNFR1 serum levels may be related to GC susceptibility.