In-silico Approach Research Articles

The assessment of the mechanism of action of lauric acid in the context of oral cancer through integrative approach combining network pharmacology and molecular docking technology.

Lauric acid has been investigated for its effects on various human cancer cell types, although limited research has been dedicated to its impact on oral cancer. In light of this, the objective of our study was to comprehensively assess the anticancer properties of lauric acid specifically in the context of oral cancer. This evaluation was achieved through an in-silico approach, leveraging network analysis techniques. By employing this methodology, we aimed to gain valuable insights into the potential therapeutic benefits of lauric acid for treating oral cancer. The in-silico analysis involved determination of drug-likeness prediction, prediction of common targets between oral cancer and LA, protein-protein interactions (PPI), hub genes, top 10 associated pathways by gene ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway, molecular docking experiments. Our study pinpointed 23 common genes involved in critical cellular processes, including proliferation, apoptosis regulation, PI3K AKT cascade, and cell cycle control. Among them, CXCL8, MMP9, PPARA, MAPK1, and AR stood out in the top 10 pathways, particularly in the PI3K/AKT signaling pathway. This highlights the potential role of lauric acid in oral cancer treatment through the PI3K/AKT pathway and calls for further exploration of this mechanism. Our study highlights lauric acid's promising anticancer properties through computational analysis, offering a foundation for future research in cancer treatment development. This approach combines molecular insights with in-silico methods, paving the way for identifying therapeutic compounds and understanding their mechanisms. Lauric acid holds potential as a chemotherapeutic agent, opening up new avenues for cancer therapy exploration.

In silico Exploration of Pharmacological and Molecular Descriptor Properties of Salacinol and Its Related Analogues

Salacinol and its related analogues have been known for their potent α-glucosidase inhibitor activity and making them interesting candidates for a new type of anti-diabetic agent. Therefore, it is essential to investigate the physicochemical properties, pharmacological parameters, and toxicity profile of these anti-diabetic agents. In this study, a comprehensive in-silico approach was used to explore the absorption, distribution, metabolism, excretion, and toxicity profiles of salacinol and its related analogues. In addition, to gain a better knowledge of structural and electrical characteristics, global and local reactivity descriptors, and molecular electrostatic potential were calculated and discussed by using DFT at the B3LYP/6–311++G (d, p) level of theory. The results explored that all the studied compounds have low GI absorption and are substrates for P-glycoprotein. None of the compounds can cross the BBB, and none of the compounds are inhibitors of cytochrome P450 isoenzymes. We also found that all compounds have various potential to interact with a wide range of biological targets, including GPCRs, enzymes, ion channels, kinases, and nuclear receptors. Additionally, all compounds have low toxicity and are unlikely to cause any major health hazards in terms of hepatotoxicity, mutagenicity, cardiotoxicity, cytotoxicity, and immunotoxicity. The molecular electrostatic potential map shows that the negative potential sites are in electronegative oxygen atoms, while the positive potential sites are around the hydrogen atoms. The present study concludes that salacinol and its analogues might be a promising safe and effective candidate for the development of therapeutic drugs derived from natural sources. However, some of their properties should be considered in the context of drug development and tissue protection strategies.

Structural, functional, molecular docking analysis of a hypothetical protein from Talaromyces marneffei and its molecular dynamic simulation: an in-silico approach

Telaromyces marneffei (formerly Penicillium marneffei) is an endemic pathogenic fungus in Southern China and Southeast Asia. It can cause disease in patients with travel-related exposure to this organism and high morbidity and mortality in acquired immune deficiency syndrome (AIDS). In this study, we analyzed the structure and function of a hypothetical protein from T. marneffei using several bioinformatics tools and servers to unveil novel pharmacological targets and design a peptide vaccine against specific epitopes. A total of seven functional epitopes were screened on the protein, and ‘STGVDMWSV’ was the most antigenic, non-allergenic and non-toxic. Molecular docking showed stronger affinity between the CTL epitope ‘STGVDMWSV’ and the MHC I allele HLA-A*02:01, a higher docking score −234.98 kcal/mol, revealed stable interactions during a 100 ns molecular dynamic simulation. Overall, the results of this study revealed that this hypothetical protein is crucial for comprehending biochemical, physiological pathways and identifying novel therapeutic targets for human health. Communicated by Ramaswamy H. Sarma

Interaction of Fe2O3 and Fe3O4 Nanoparticle with Pathogenic Bacteria: A In-silico Molecular Mechanism Study

Background:: Magnetic materials like iron, nickel, and cobalt have been a subject of interest among the scientific and research community for centuries. Owing to their unique properties, they are prevalent in the mechanical and electronic industries. In recent times, magnetic materials have undeniable applications in biotechnology and nanomedicine. Bacteria like Salmonella enterica, Clostridium botulinum, Bacillus subtilis, etc, pose a hazard to human health and livestock. This ultimately leads to huge yields and economic losses on a global scale. Antimicrobial resistance has become a significant public health concern in recent years, with the increasing prevalence of drugresistant infections posing a significant threat to global health. Many coherent studies have successfully reported magnetic metal oxide nanoparticles to be highly selective, specific, and effective in neutralizing pathogens through various mechanisms like cell membrane disruption, direct contact-mediated killing, or by generating Reactive Oxygen Species (ROS) and numerous costimulatory and inflammatory cytokines. Therefore, we explored the inhibitory effects of iron oxide nanoparticles (NPs) on various pathogenic bacteria via an in-silico approach. This method helped us to understand the active sites where the iron oxide NPs bind with the bacterial proteins. Methods:: The 3D crystal structures of all the pathogenic proteins of Streptococcus pneumoniae, Pseudomonas aeruginosa, Vibrio cholerae, Salmonella enterica, Shigella flexneri, Clostridium botulinum and nanoparticles (Fe2O3 and Fe3O4) under study were downloaded from RCSB PDB and ChemSpider official websites respectively. It was followed by the in-silico molecular Docking using PyRx and AutoDock Vina and analyzed on LigPlot. Results:: This study interprets the efficacy of the Fe2O3 and Fe3O4 nanoparticles against all the test bacteria. At the same time, Fe2O3 and Fe3O4 formed the most stable complexes with cholera enterotoxin subunit B and lectin II (PA-IIL) mutant S23A of Pseudomonas aeruginosa, respectively. Conclusion:: As in this era of AMR, researchers have been exploring alternative strategies to combat bacterial infections, including using magnetic nanoparticles as a potential treatment. They possess unique physical and chemical properties that make them attractive candidates for antimicrobial therapy, including their ability to penetrate bacterial biofilms and selectively target pathogenic bacteria while leaving healthy cells unharmed. This study examined the inhibitory effects of iron oxide (magnetic) nanoparticles, namely Fe2O3 and Fe3O4, on various bacterial proteins involved in cell-to-cell interactions and pathogenesis.

In-silico, Synthesis, Characterization, and In-vitro Studies on Benzylidene-based 2-chloroquinolin Derivatives as Free Radical Scavengers in Parkinson's Disease.

Parkinson's disease is the loss of dopaminergic neurons in the substantial nigra part of the brain leading to neurodegeneration. Whereas, reactive oxygen species and mitochondrial impairment are considered to be the major pathophysiology of neurodegeneration. The benzylidene-based 2-chloroquinolin derivatives were synthesized and characterized by FT-IR, NMR, and MS spectrometry which were screened using various in-silico approaches. The designed compounds were further assessed using in-vitro cytotoxicity assay by the MTT method, DPPH assay, and Glutathione measurements in the SHSY5Y neuroblastoma cell lines. The compounds JD-7 and JD-4 were found to have a binding affinity of - 7.941 and - 7.633 kcal/mol with an MMGBSA score of - 64.614 and - 62.817 kcal/mol. The compound JD-7 showed the highest % Cell viability of 87.64% at a minimal dose of 125 µg/mL by the MTT method. The neurotoxicity effects were observed at increasing concentrations from 0 to 125, 250, and 500 µg/mL. Further, free radical scavenging activity for the JD-7 was found to be 36.55 at lowest 125 µg/mL concentrations. At 125 µg/mL, GSH % and GSSG % were found to be increasing in rotenone treatment, whereas JD-7 and JD-4 were found in the downregulation of glutathione level in the pre-treated rotenone SHSY5Y neuroblastoma cell lines. The benzylidene-based chloroquinolin derivatives were synthesized, and among the compounds JD-1 to JD-13, the compounds JD-7, and JD-4 were found to have having highest % cell viability, free radical scavenging molecules, and glutathione levels in the SHSY5Y neuroblastoma cell lines and could be used as free radical scavengers in Parkinson's disease.

Novel 1-H Phenyl Benzimidazole Derivatives for IBD Therapy - An in-vitro and in-silico Approach to Evaluate its Effects on the IL-23 Mediated Inflammatory Pathway.

IBD is a chronic idiopathic gut condition characterised by recurring and remitting inflammation of the colonic mucosal epithelium. Benzimidazole is a prominent and attractive heterocyclic compound with diverse actions. Although seven locations in the benzimidazole nucleus can be changed with a number of chemical entities for biological activity, benzimidazole fused with a phenyl ring has caught our interest. To find and optimize novel 1-H phenyl benzimidazole compounds with favorable physicochemical features and drug-like characteristics for the treatment of IBD, in-silico studies and in-vitro approach were being used to identify and optimize these derivatives as potent inhibitors of IL-23 mediated inflammatory signaling pathway. All six compounds exhibit favorable drug-like properties with good intestinal absorption properties. Its high affinity for the target JAK and TYK, which is thought to be a key immunological signaling cascade in the pathophysiology of IBD, is revealed by docking studies. Because of their effects on decreasing iNOS-derived NO release and IL-23-mediated immune signaling by decreasing COX-2 and LOX activity, it's conceivable that the compounds CS3 and CS6 are better options for the treatment of IBD based on in-vitro cell line investigations.

Evaluation of novel Anti-SARS-CoV-2 compounds by targeting nucleoprotein and envelope protein through homology modeling, docking simulations, ADMET, and molecular dynamic simulations with the MM/GBSA calculation

The current prominent virus that induces severe acute respiratory syndrome is SARS-CoV-2. The incidence of COVID-19 cases is increasing, necessitating the immediate development of effective treatments. Our objective was to employ an in-silico approach to evaluate the effectiveness of conventional compounds against COVID-19's nucleoprotein and envelope protein. A docking simulation was performed on 9 compounds as SARS-coronavirus inhibitors using AMDock software. Anti-covid-19 activities were further evaluated for the compounds. Based on docking results, the binding affinity of "N-(4-carbamoylphenyl)-8-cyclopropyl-7-(naphthalen-1-ylmethyl)-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxamide,” also called compound 36 in this research, was found to be −8.8 ​kcal/mol for the modeled envelope protein and −7.3 ​kcal/mol for the template envelope protein, while −10.1 ​kcal/mol for the modeled nucleocapsid proteins (NP) and −8.7 ​kcal/mol for the template nucleocapsid proteins (NP) of SARS-coronavirus, respectively. The ligand and control drug (ritonavir) with high docking scores were subjected to pharmacological screening, molecular dynamic simulations, and Molecular Mechanics-generalized Born Surface Area (MM/GBSA) calculations. Furthermore, the jobs of pharmacokinetics were assessed, and the outcomes acquired show that the proposed compound 36 includes great oral bioavailability and a capacity to diffuse through various organic boundaries. The protein-ligand complexes were subjected to dynamic simulation analyses with a re-enactment time of 10 ns, likewise, their free binding energy was inspected operating the MM/GBSA approach. The docking (MD simulation) results acquired emphasize the pivotal residues answerable for the protein-ligand interaction, giving an understanding of the method of association. The MD simulation analysis verifies the structural stability of the selected complexes during the MD trajectory, with minor changes detected. The MM/GBSA data show that compound 36 has the lowest free energy of −12.498 ​kcal/mol for EP and −57.5185 ​kcal/mol for NP proteins of SARS-coronavirus, confirming the molecular docking result. As a result, the identified chemical can be used to develop a new family of antiviral medications against SARS-coronavirus-2.

In-silico Approach to Investigate the Phytochemicals of Terminalia arjuna as Multitarget Inhibitors of Proteins Involved with Lung Cancer

Background: Existing medications for treating cancer are reported to exhibit severe side effects, therefore, there is an urgent need to address these unprecedented health risks. With the advancements in ethnobotanical studies and research on phytochemicals, information on several medicinal plants is being revisited nowadays. Terminalia arjuna is a widely used medicinal plant in ayurvedic and Unani medicine for curing several diseases. Although the bioactives from this plant are reported to possess anticarcinogenic, antiproliferative and antioxidant activities, information on the potentials of its specific phytoconstituents on the inhibition of receptor molecules associated with lung cancer is scarce. Objectives: The primary goal of this study is to virtually screen the phytochemicals of Terminalia arjuna as potential drug candidate molecules for lung cancer. Considering all major reported receptor molecules that inevitably take part in lung cancer, it highlights the phytochemicals as novel multitargeted inhibitors of proteins responsible for lung cancer. Methods: A thorough literature review was done to select twenty-seven receptor molecules associated with lung cancer cases. The molecular docking study using PyRx predicts protein-ligand interactions and identifies potential drug targets. Evaluating the ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of the phytochemicals present in Terminalia arjuna, this study takes into account thirty-four bioactive compounds as the chosen ligands in molecular docking. The binding affinity, inhibition constant (Ki), and the interacting residues of these phytochemicals with the receptors are compared with the docking results of twelve selected standard anticancer drugs. The study finally categorizes the phytochemicals that can potentially act as multitargeted inhibitors of proteins associated with lung cancer. Results: The results from PyRx highlighted the phytoconstituents having a higher binding affinity with inhibition constant comparable to the standard drugs. Among the standard anticancer drugs, alectinib, pralsetinib, and ibrutinib are marked as potent inhibitors of several lung cancer receptors. The phytochemicals of Terminalia arjuna proved to be the potential candidates against ALK2, ALK5, DDR2, BRAF, KRAS, Tankyrase, vasopressin V2, VEGFR1 and VEGFR2 mediated lung cancer but the effectiveness (in comparison to the standard drugs) is limited against Bcl-2, IL22R1, NCAM, RET, MET and ROS1 receptors. Conclusions: The findings indicate that phytochemicals namely luteolin, friedelin, oleanolic acid, and 14,16-dianhydrogitoxigenin bind strongly to multiple receptors under consideration with high affinity and hence could be investigated as effective alternatives for treating lung cancer with minimal side effects.

THE EFFECT OF THE D185 MUTATION ON THE STABILITY AND FUNCTIONALITY OF RUBISCO LIKE PROTEIN (RLP) FROM CHROMOHALOBACTER SALEXIGEN BKL 5

THE EFFECT OF THE D185 MUTATION ON THE STABILITY AND FUNCTIONALITY OF RUBISCO LIKE PROTEIN (RLP) FROM CHROMOHALOBACTER SALEXIGEN BKL 5

Identification of cancer inhibitors from Hystrix brachyurabezoar extracts using LC-MS multivariate data analysis and in silico evaluation on Bcl-2, cyclin B/CDK1, VEGF and NM23-H1

Hystrix brachyurabezoar is calcified undigested material found in the gastrointestinal tract known for various medicinal benefits including as an anticancer agent. However, the H. brachyurapopulation has been declining due to its demand and is under Malaysian law protection. Therefore, present study aimed to identify bezoar anticancer active compounds through metabolomics and in-silico approaches. Five replicates of bezoar powder were subjected to extraction using different solvent ratios of methanol-water (100, 75, 50, 25, 0% v/v). Cytotoxicity and metabolite profiling using liquid chromatography-mass spectrometry were conducted. Putative compounds identified were subjected to in-silico analysis with targeted anticancer proteins namely, Bcl-2, Cyclin B/CDK1 complex, VEGF and NM23-H1. The correlation of LC-MS and cytotoxicity profile pinpointed two compounds, mangiferin and propafenone. In-silicostudy showed both compounds exerted good binding scores to all proteins with hydrophobic interaction dominating the ligand-protein complex binding, suggesting the ligands act as hydrophobes in the interactions.

Role of biomarkers and molecular signaling pathways in acute lung injury.

Acute lung injury (ALI) is caused by bacterial, fungal, and viral infections. When pathogens invade the lungs, the immune system responds by producing cytokines, chemokines, and interferons to promote the infiltration of phagocytic cells, which are essential for pathogen clearance. Their excess production causes an overactive immune response and a pathological hyper-inflammatory state, which leads to ALI. Until now, there is no particular pharmaceutical treatment available for ALI despite known inflammatory mediators like neutrophil extracellular traps (NETs) and reactive oxygen species (ROS). Therefore, the primary objective of this review is to provide the clear overview on the mechanisms controlling NETs, ROS formation, and other relevant processes during the pathogenesis of ALI. In addition, we have discussed the significance of epithelial and endothelial damage indicators and several molecular signaling pathways associated with ALI. The literature review was done from Web of Science, Scopus, PubMed, and Google Scholar for ALI, NETs, ROS, inflammation, biomarkers, Toll- and nucleotide-binding oligomerization domain (NOD)-like receptors, alveolar damage, pro-inflammatory cytokines, and epithelial/endothelial damage alone or in combination. This review summarized the main clinical signs of ALI, including the regulation and distinct function of epithelial and endothelial biomarkers, NETs, ROS, and pattern recognition receptors (PRRs). However, no particular drugs including vaccine for ALI has been established. Furthermore, there is a lack of validated diagnostic tools and a poor predictive rationality of current therapeutic biomarkers. Hence, extensive and precise research is required to speed up the process of drug testing and development by the application of artificial intelligence technologies, structure-based drug design, in-silico approaches, and drug repurposing.

Unveiling the structure and interactions of SOG1, a NAC domain transcription factor: An in-silico perspective

SOG1 is a crucial plant-specific NAC domain family transcription factor and functions as the central regulator of DNA damage response, acting downstream of ATM and ATR kinases. In this study, various in-silico approaches have been employed for the characterization of SOG1 transcription factor in a comparative manner with its orthologues from various plant species. Amino acid sequences of more than a hundred SOG1 or SOG1-like proteins were retrieved and their relationship was determined through phylogenetic and motif analyses. Various physiochemical properties and secondary structural components of SOG1 orthologues were determined in selective plant species including Arabidopsis thaliana, Oryza sativa, Amborella trichopoda, and Physcomitrella patens. Furthermore, fold recognition or threading and homology-based three-dimensional models of SOG1 were constructed followed by subsequent evaluation of quality and accuracy of the generated protein models. Finally, extensive DNA-Protein and Protein-Protein interaction studies were performed using the HADDOCK server to give an insight into the mechanism of how SOG1 binds with the promoter region of its target genes or interacts with other proteins to regulate the DNA damage responses in plants. Our docking analysis data have shown the molecular mechanism of SOG1′s binding with 5′-CTT(N)7AAG-3′ and 5′-(N)4GTCAA(N)4-3′ consensus sequences present in the promoter region of its target genes. Moreover, SOG1 physically interacts and forms a thermodynamically stable complex with NAC103 and BRCA1 proteins, which possibly serve as coactivators or mediators in the transcription regulatory network of SOG1. Overall, our in-silico study will provide meaningful information regarding the structural and functional characterization of the SOG1 transcription factor.

In-vitro antimicrobial activity of AF-DP protein and in-silico approach of cell membrane disruption

Microbial resistance against common antibiotics has become one of the most serious threats to human health. The increasing statistics on this problem show the necessity of finding a way to deal with it. In recent years, antimicrobial peptides with unique properties and the capability of targeting a wide range of pathogens, have been considered as a potential for replacing common antibiotics. A small chitin-binding protein with anticandidal activity was isolated from Moringa oleifera seeds by Neto and colleagues in 2017, which very much resembled antimicrobial peptides. In this study, the antimicrobial protein ‘AF-DP’ was identified and characterized. AF-DP was heterologously expressed, purified, and characterized, and its 3D structure was predicted. Six molecular dynamic simulations were performed to investigate how the protein interacts with Gram-negative inner and outer, Gram-positive, fungal, cancerous, and normal mammalian membranes. Also, its antimicrobial and anticancer activity was assessed in vitro via minimum inhibition concentration (MIC) and MTT assays, respectively. This protein with 111 amino acids and a total net charge (of 10.5) has been predicted to be mainly composed of alpha helix and random coils. Its MIC affecting the growth of Escherichia coli, Staphylococcus aureus, and Candida albicans was 30 µg/ml, 100 µg/ml, and 100 µg/ml, respectively; AF-DP showed anticancer activity against MCF-7 breast cancer cell line. Scanning electron microscopic analysis confirmed the creation of pores and scratches on the surface of the bacterial membrane. The results of this research show that AF-DP can be a candidate for the production of new drugs as an AMP with antimicrobial activity. Communicated by Ramaswamy H. Sarma

FBXW7 polymorphism asserts susceptibility to colorectal cancer

FBXW7, belonging to the F-Box protein family, is considered a candidate cancer susceptibility gene. Our findings indicate that single nucleotide polymorphisms (SNPs) in the FBXW7 gene are linked to cancer risk, strengthening FBXW7′s role in the pathogenesis of colorectal cancer. Our case-control study comprised of 450 patients diagnosed with colorectal cancer (CRC) and an equal number of 450 healthy subjects. FBXW7 SNPs rs2255137C>T and rs6842544C>T were genotyped using PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) and Single-Stranded Conformation Polymorphism (SSCP) techniques and further cross-checked by direct sequencing. Linkage disequilibrium and haplotype analyses of these SNPs were also assessed. The in-silico approach was used to reveal the functional analysis between the nonsynonymous variation (rs6842544) and CRC followed by its validation at the protein level by western blotting and reverse transcription-PCR. A significant association of colorectal cancer was detected with rs6842544 SNP. However, there was no association between FBXW7 rs2255137 polymorphism and CRC. The homozygous individuals carrying the C variant in FBXW7 rs6842544 showed a slightly higher risk for colorectal cancer (OR = 1.590, 95%CI = 0.39 ∼ 2.89, p = 0.011). The haplotype CC identified in this study seemed to be associated with good prognosis (OR = 1.22, 95% CI = 1.00 ∼ 1.47, p = 0.0013) whereas the TT haplotype was found to reduce the CRC risk (OR = 0.642, 95%CI = 0.48 ∼ 0.84, p = 0.039). In-silico prediction proposed that the variant R133G is responsible for the lower expression of FBXW7. Additionally, the expression profiling of FBXW7 nonsynonymous SNP was significantly lower in primary CRC tissues than in the paired non-cancerous tissues at protein and mRNA levels. The study indicates that the FBXW7 rs6842544 is associated with the risk of development of CRC and could serve as a molecular biological marker to screen high-risk groups for CRC.

Structure-based virtual screening study for identification of potent insecticides against the Anopheles gambiae to combat the malaria.

Vector-borne infectious diseases contribute significantly to global mortality, with over 700,000 annual deaths, and malaria alone accounts for more than 400,000 of these fatalities. Anopheles gambiae, a prominent mosquito species, serves as a primary vector for transmitting malaria to humans. To address this issue, researchers have identified the D1-like dopamine receptor (DAR), specifically DOP2, as a promising target for developing new insecticides. The three-dimensional structure of DOP2 from A. gambiae was unavailable in the PDB database, an in-silico approach was used to model and validate the DOP2 protein's structure. The Discovery Studio 2021 program was then used to identify potential binding sites on the DOP2 protein. A virtual screening of 235 anti-parasitic compounds was performed against DOP2 using PyRx 0.8. The screening demonstrated strong binding and interactions with active site residues of the DOP2 protein for five compounds: Diclazuril, Kaempferol, Deracoxib, Clindamycin, and Diaveridine. These compounds exhibited higher binding affinity values compared to the control (Asenapine). In addition, the predicted physiochemical properties for these compounds were within acceptable ranges, and there were no violations in druglikeness properties. These compounds show promise as potential new insecticides targeting the A. gambiae mosquito by inhibiting the DOP2 protein. However, additional experimental validation is required to optimize their efficacy as DOP2 protein inhibitors.

Structural and Functional Characterization of Biofilm-Related Proteins of Mycobacterium spp: An in-silico Approach

Biofilm-associated infections are characterized by the chronicity, recurrence, and the requirement of a prolonged administration of multiple drugs. Several non-pathogenic and pathogenic species of microorganism including Mycobacteria spp form biofilm. Mycobacterial biofilms present a unique composition. Instead of exopolysaccharides in other bacteria, proteins are essential compounds of the biofilm matrix in mycobacteria. To tackle mycobacterial infections, a detailed understanding of the biofilm-forming mechanisms is crucial. In this present study, all available Mycobacterial proteins involved in the biofilm were selected. Their sequences were retrieved and characterized through the determination of their physicochemical properties, secondary structure, 3D structure, subcellular localization, conserved domain, ubiquitination sites, and virulence potentiality. Furthermore, druggability testing was undertaken after excluding proteins with homology to human proteins to identify possible drug targets. The results showed that they possess functionally important domains and families. All of the selected hypothetical proteins were stable. Six of them were classified as soluble and the remaining as transmembrane proteins. A sole protein was found to lack ubiquitination sites. Additionally, three of these were discovered to be virulent. Moreover, host non-homology results indicated eight pathogen-specific proteins that might be potential therapeutic targets. Among them, D-alanyl-D-alanine carboxypeptidase is a druggable target that is inhibited by beta-lactam antibiotics. The remainder of the proteins were categorized as new targets. 
 In conclusion, this study may increase our knowledge of pathogenesis and host adaptation, drug resistance, and identification of drug and vaccine targets against infections caused by Mycobacteria. It can also guide new research.

Ligand-Based Design of Novel Quinoline Derivatives as Potential Anticancer Agents: An In-Silico Virtual Screening Approach.

In this study, using the Comparative Molecular Field Analysis (CoMFA) approach, the structure-activity relationship of 33 small quinoline-based compounds with biological anti-gastric cancer activity in vitro was analyzed in 3D space. Once the 3D geometric and energy structure of the target chemical library has been optimized and their steric and electrostatic molecular field descriptions computed, the ideal 3D-QSAR model is generated and matched using the Partial Least Squares regression (PLS) algorithm. The accuracy, statistical precision, and predictive power of the developed 3D-QSAR model were confirmed by a range of internal and external validations, which were interpreted by robust correlation coefficients (RTrain2=0.931; Qcv2=0.625; RTest2=0.875). After carefully analyzing the contour maps produced by the trained 3D-QSAR model, it was discovered that certain structural characteristics are beneficial for enhancing the anti-gastric cancer properties of Quinoline derivatives. Based on this information, a total of five new quinoline compounds were developed, with their biological activity improved and their drug-like bioavailability measured using POM calculations. To further explore the potential of these compounds, molecular docking and molecular dynamics simulations were performed in an aqueous environment for 100 nanoseconds, specifically targeting serine/threonine protein kinase. Overall, the new findings of this study can serve as a starting point for further experiments with a view to the identification and design of a potential next-generation drug for target therapy against cancer.

New light on the HLA-DR immunopeptidomic landscape.

The set of peptides processed and presented by major histocompatibility complex class II molecules defines the immunopeptidome, and its characterization holds keys to understanding essential properties of the immune system. High-throughput mass spectrometry (MS) techniques enable interrogation of the diversity and complexity of the immunopeptidome at an unprecedented scale. Here, we analyzed a large set of MS immunopeptidomics data from 40 donors, 221 samples, covering 30 unique HLA-DR molecules. We identified likely co-immunoprecipitated HLA-DR irrelevant contaminants using state-of-the-art prediction methods and unveiled novel light on the properties of HLA antigen processing and presentation. The ligandome (HLA binders) was enriched in 15-mer peptides, and the contaminome (nonbinders) in longer peptides. Classification of singletons and nested sets showed that the first were enriched in contaminants. Investigating the source protein location of ligands revealed that only contaminants shared a positional bias. Regarding subcellular localization, nested peptides were found to be predominantly of endolysosomal origin, whereas singletons shared an equal distribution between the cytosolic and endolysosomal origin. According to antigen-processing signatures, no significant differences were observed between the cytosolic and endolysosomal ligands. Further, the sensitivity of MS immunopeptidomics was investigated by analyzing overlap and saturation between biological MS replicas, concluding that at least 5 replicas are needed to identify 80% of the immunopeptidome. Moreover, the overlap in immunopeptidome between donors was found to be very low both in terms of peptides and source proteins, the latter indicating a critical HLA bias in the antigen sampling in the HLA antigen presentation. Finally, the complementarity between MS and in silico approaches for comprehensively sampling the immunopeptidome was demonstrated.

Virtual screening and pharmacokinetics analysis of inhibitors against tuberculosis: Structure and ligand-based approach

Life-threatening diseases like tuberculosis have raised concerns in the medical and scientific communities. The damage-causing disease makes the scientific community employ the in-silico approach for design of new inhibitors that can inhibit or retard the havoc caused by this deadly disease. The insilico approach was used in this study to create a mathematical model with promising molecular properties, and receptors from the library were used to screen compounds and estimate the kinetic ability of the screened inhibitors that can cure this disease. 2D molecular properties evolved in the built model with high predictive ability. Three inhibitors x, y, and z emerged with better and higher molecular properties, the lowest binding energy (and higher binding affinity), and a better pharmacokinetic assessment compared to the template used in designing the effective compounds, with binding affinities of -15.56 kcal/mol, -18.51 kcal/mol, and -18.58 kcal/mol, respectively. Virtual screening of these compounds showed that they have good binding energy and excellent docking positions with the inhibiting potential of the receptor. Also, pharmacokinetic predictions and ADMET, depict orally active ability of the inhibitors, possess good human intestinal absorption, and violate none of the RO5 as potential drug candidates to cure this disease. Hence, further laboratory tests are recommended for these to determine their toxicities and biological assays.

Profibrotic Subsets of SPP1+ Macrophages and POSTN+ Fibroblasts Contribute to Fibrotic Scarring in Acne Keloidalis

Acne keloidalis is a primary scarring alopecia characterized by longstanding inflammation in the scalp causing keloid-like scar formation and hair loss. Histologically, acne keloidalis is characterized by mixed leukocytic infiltrates in the acute stage followed by a granulomatous reaction and extensive fibrosis in the later stages. To further explore its pathogenesis, bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics were applied to occipital scalp biopsy specimens of lesional and adjacent no-lesional skin in patients with clinically active disease. Unbiased clustering revealed 19 distinct cell populations, including 2 notable populations: POSTN+ fibroblasts with enriched extracellular matrix signatures and SPP1+ myeloid cells with an M2 macrophage phenotype. Cell communication analyses indicated that fibroblasts and myeloid cells communicated by SPP1 signaling networks in lesional skin. A reverse transcriptomics in silico approach identified corticosteroids as possessing the capability to reverse the gene expression signatures of SPP1+ myeloid cells and POSTN+ fibroblasts. Intralesional corticosteroid injection greatly reduced SPP1 and POSTN gene expression as well as acne keloidalis disease activity. Spatial transcriptomics and immunofluorescence staining verified microanatomic specificity of SPP1+ myeloid cells and POSTN+ fibroblasts with disease activity. In summary, the communication between POSTN+ fibroblasts and SPP1+ myeloid cells by SPP1 axis may contribute to the pathogenesis of acne keloidalis.