Bioinformatics and Biology Insights最新文献

{"title":"Investigation of Methyl-5-(pentan-3-yloxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxyhydrazide Derivatives as Potential Inhibitors of COVID-19 Main Protease: DFT and Molecular Docking Study.","authors":"Olawale Folorunso Akinyele,&nbsp;Emmanuel Gabriel Fakola,&nbsp;Omolara Olubunmi Adeboye,&nbsp;Sunday Chimela Chinuomah","doi":"10.1177/11779322231182050","DOIUrl":"10.1177/11779322231182050","url":null,"abstract":"<p><p>The search for effective therapeutics to combat COVID-19 has led to the exploration of the biological activity of numerous compounds. In this study, hydrazones derived from oseltamivir intermediate, methyl 5-(pentan-3-yloxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate have been investigated for their potential as drug candidates against the COVID-19 virus using computational methods, including density functional theory (DFT) studies, molecular docking, and absorption, distribution, metabolism, excretion and toxicity (ADMET) analysis. The DFT studies provide information on the electronic properties of the compounds while the molecular docking results using AutoDock reported the binding energies between the main protease of COVID-19 and the compounds. The DFT results revealed that the energy gap of the compounds ranged from 4.32 to 5.82 eV while compound HC had the highest energy gap (5.82 eV) and chemical potential (2.90 eV). The electrophilicity index values of the 11 compounds ranged from 2.49 to 3.86, thus they were classified as strong electrophiles. The molecular electrostatic potential (MESP) revealed electron-rich and electron-deficient regions of the compounds. The docking results reveal that all the compounds had better docking scores than remdesivir and chloroquine, frontline drugs employed in combating COVID-19, with HC having the best docking score of -6.5. The results were visualized using Discovery studio, which revealed hydrogen bonding, pi-alkyl interaction, alkyl interaction, salt bridge interaction, halogen interaction as being responsible for the docking scores. The drug-likeness results showed that the compounds qualify as oral drug candidates as none of them violated Vebers and Lipinski's rule. Thus, they could serve as potential inhibitors of COVID-19.</p>","PeriodicalId":9065,"journal":{"name":"Bioinformatics and Biology Insights","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2023-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/74/75/10.1177_11779322231182050.PMC10291222.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9724400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"COVID-19 Epidemic Forecast in Brazil.","authors":"Oleg Gaidai, Yihan Xing","doi":"10.1177/11779322231161939","DOIUrl":"10.1177/11779322231161939","url":null,"abstract":"<p><p>This study advocates a novel spatio-temporal method for accurate prediction of COVID-19 epidemic occurrence probability at any time in any Brazil state of interest, and raw clinical observational data have been used. This article describes a novel bio-system reliability approach, particularly suitable for multi-regional environmental and health systems, observed over a sufficient time period, resulting in robust long-term forecast of the virus outbreak probability. COVID-19 daily numbers of recorded patients in all affected Brazil states were taken into account. This work aimed to benchmark novel state-of-the-art methods, making it possible to analyse dynamically observed patient numbers while taking into account relevant regional mapping. Advocated approach may help to monitor and predict possible future epidemic outbreaks within a large variety of multi-regional biological systems. Suggested methodology may be used in various modern public health applications, efficiently using their clinical survey data.</p>","PeriodicalId":9065,"journal":{"name":"Bioinformatics and Biology Insights","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c3/9b/10.1177_11779322231161939.PMC10090958.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9373160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of <i>CDKL5</i>-Deficiency Disorders.","authors":"Ibitayo Abigail Ademuwagun, Gbolahan Oladipupo Oduselu, Solomon Oladapo Rotimi, Ezekiel Adebiyi","doi":"10.1177/11779322231158254","DOIUrl":"10.1177/11779322231158254","url":null,"abstract":"<p><p>Therapeutic intervention in cyclin-dependent kinase-like 5 (CDKL5) deficiency disorders (CDDs) has remained a concern over the years. Recent advances into the mechanistic interplay of signalling pathways has revealed the role of deficient tropomyosin receptor kinase B (TrkB)/phospholipase C γ1 signalling cascade in CDD. Novel findings showed that in vivo administration of a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), resulted in a remarkable reversal in the molecular pathologic mechanisms underlying CDD. Owing to this discovery, this study aimed to identify more potent TrkB agonists than 7,8-DHF that could serve as alternatives or combinatorial drugs towards effective management of CDD. Using pharmacophore modelling and multiple database screening, we identified 691 compounds with identical pharmacophore features with 7,8-DHF. Virtual screening of these ligands resulted in identification of at least 6 compounds with better binding affinities than 7,8-DHF. The in silico pharmacokinetic and ADMET studies of the compounds also indicated better drug-like qualities than those of 7,8-DHF. Postdocking analyses and molecular dynamics simulations of the best hits, 6-hydroxy-10-(2-oxo-1-azatricyclo[7.3.1.05,13]trideca-3,5(13),6,8-tetraen-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem: 91637738) and 6-hydroxy-10-(8-methyl-2-oxo-1H-quinolin-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem ID: 91641310), revealed unique ligand interactions, validating the docking findings. We hereby recommend experimental validation of the best hits in CDKL5 knock out models before consideration as drugs in CDD management.</p>","PeriodicalId":9065,"journal":{"name":"Bioinformatics and Biology Insights","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/bb/c5/10.1177_11779322231158254.PMC9989394.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9437716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Insight Into Mechanisms of Hepatic Encephalopathy: An Integrative Analysis Approach to Identify Molecular Markers and Therapeutic Targets.","authors":"Ali Sepehrinezhad, Ali Shahbazi, Sajad Sahab Negah, Fin Stolze Larsen","doi":"10.1177/11779322231155068","DOIUrl":"10.1177/11779322231155068","url":null,"abstract":"<p><p>Hepatic encephalopathy (HE) is a set of complex neurological complications that arise from advanced liver disease. The precise molecular and cellular mechanism of HE is not fully understood. Differentially expressed genes (DEGs) from microarray technologies are powerful approaches to obtain new insight into the pathophysiology of HE. We analyzed microarray data sets of cirrhotic patients with HE from Gene Expression Omnibus to identify DEGs in postmortem cerebral tissues. Consequently, we uploaded significant DEGs into the STRING to specify protein-protein interactions. Cytoscape was used to reconstruct the genetic network and identify hub genes. Target genes were uploaded to different databases to perform comprehensive enrichment analysis and repurpose new therapeutic options for HE. A total of 457 DEGs were identified in 2 data sets totally from 12 cirrhotic patients with HE compared with 12 healthy subjects. We found that 274 genes were upregulated and 183 genes were downregulated. Network analyses on significant DEGs indicated 12 hub genes associated with HE. Enrichment analysis identified fatty acid beta-oxidation, cerebral organic acidurias, and regulation of actin cytoskeleton as main involved pathways associated with upregulated genes; serotonin receptor 2 and ELK-SRF/GATA4 signaling, GPCRs, class A rhodopsin-like, and p38 MAPK signaling pathway were related to downregulated genes. Finally, we predicted 39 probable effective drugs/agents for HE. This study not only confirms main important involved mechanisms of HE but also reveals some yet unknown activated molecular and cellular pathways in human HE. In addition, new targets were identified that could be of value in the future study of HE.</p>","PeriodicalId":9065,"journal":{"name":"Bioinformatics and Biology Insights","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3f/20/10.1177_11779322231155068.PMC9940182.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10764638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In silico</i> Structure Prediction, Molecular Docking, and Dynamic Simulation of <i>Plasmodium falciparum</i> AP2-I Transcription Factor.","authors":"David O Oladejo, Gbolahan O Duselu, Titilope M Dokunmu, Itunuoluwa Isewon, Jelili Oyelade, Esther Okafor, Emeka Ej Iweala, Ezekiel Adebiyi","doi":"10.1177/11779322221149616","DOIUrl":"10.1177/11779322221149616","url":null,"abstract":"<p><p><i>Plasmodium falciparum</i> Apicomplexan Apetala 2 Invasion (<i>Pf</i>AP2-I) transcription factor (TF) is a protein that regulates the expression of a subset of gene families involved in <i>P. falciparum</i> red blood cell (RBC) invasion. Inhibiting <i>Pf</i>AP2-I TF with small molecules represents a potential new antimalarial therapeutic target to combat drug resistance, which this study aims to achieve. The 3D model structure of <i>Pf</i>AP2-I was predicted <i>ab initio</i> using ROBETTA prediction tool and was validated using Save server 6.0 and MolProbity. Computed Atlas of Surface Topography of proteins (CASTp) 3.0 was used to predict the active sites of the <i>Pf</i>AP2-I modeled structure. Pharmacophore modeling of the control ligand and <i>Pf</i>AP2-I modeled structure was carried out using the Pharmit server to obtain several compounds used for molecular docking analysis. Molecular docking and postdocking studies were conducted using AutoDock vina and Discovery studio. The designed ligands' toxicity predictions and <i>in silico</i> drug-likeness were performed using the SwissADME predictor and OSIRIS Property Explorer. The modeled protein structure from the ROBETTA showed a validation result of 96.827 for ERRAT, 90.2% of the amino acid residues in the most favored region for the Ramachandran plot, and MolProbity score of 1.30 in the 98th percentile. Five (5) best hit compounds from molecular docking analysis were selected based on their binding affinity (between -8.9 and -11.7 Kcal/mol) to the active site of <i>Pf</i>AP2-I and were considered for postdocking studies. For the absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties, compound MCULE-7146940834 had the highest drug score (0.63) and drug-likeness (6.76). MCULE-7146940834 maintained a stable conformation within the flexible protein's active site during simulation. The good, estimated binding energies, drug-likeness, drug score, and molecular dynamics simulation interaction observed for MCULE-7146940834 against <i>Pf</i>AP2-I show that MCULE-7146940834 can be considered a lead candidate for <i>Pf</i>AP2-I inhibition. Experimental validations should be carried out to ascertain the efficacy of these predicted best hit compounds.</p>","PeriodicalId":9065,"journal":{"name":"Bioinformatics and Biology Insights","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2023-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/14/a7/10.1177_11779322221149616.PMC9871981.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10625593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel c.100C > G Mutation in the <i>FST</i> Gene and Its Relation With the Reproductive Traits of Awassi Ewes.","authors":"Tahreer M Al-Thuwaini,&nbsp;Wefak J Albazi,&nbsp;Mohammed Baqur S Al-Shuhaib,&nbsp;Layth H Merzah,&nbsp;Rihab G Mohammed,&nbsp;Fadhil A Rhadi,&nbsp;Ali B Abd Al-Hadi,&nbsp;Ahmed H Alkhammas","doi":"10.1177/11779322231170988","DOIUrl":"https://doi.org/10.1177/11779322231170988","url":null,"abstract":"<p><p>Reproductive traits are affected by many factors, including ovarian function, hormones, and genetics. Genetic polymorphisms of candidate genes are associated with reproductive traits. Several candidate genes are associated with economic traits, including the follistatin (<i>FST</i>) gene. Thus, this study aimed to evaluate whether the genetic variations in the <i>FST</i> gene are associated with the reproductive traits in Awassi ewes. The genomic DNA was extracted from 109 twin ewes and 123 single-progeny ewes. Therefore, 4 sequence fragments from the <i>FST</i> gene were amplified using polymerase chain reaction (PCR) (exon 2/240, exon 3/268, exon 4/254, and exon 5/266 bp, respectively). For a 254 bp amplicon, 3 genotypes were identified: CC, CG, and GG. Sequencing revealed a novel mutation in CG genotypes c.100C > G. The statistical analysis of c.100C > G showed an association with reproductive characteristics. Ewes carrying the c.100C > G had significantly (<i>P</i> ⩽ .01) lower litter sizes, twinning rates, lambing rates, and more days to lambing compared with CG and CC genotypes. Logistic regression analysis confirmed that the c.100C > G single-nucleotide polymorphism (SNP) is responsible for decreasing litter size. According to these results, the variant c.100C > G negatively affects the traits of interest and is associated with lower reproductive traits in Awassi sheep. As a result of this study, ewes carrying the c.100C > G SNP have lower litter size and are less prolific.</p>","PeriodicalId":9065,"journal":{"name":"Bioinformatics and Biology Insights","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6f/0a/10.1177_11779322231170988.PMC10159244.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9433084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential Biomarkers for Parkinson Disease from Functional Enrichment and Bioinformatic Analysis of Global Gene Expression Patterns of Blood and Substantia Nigra Tissues.","authors":"Ramu Elango,&nbsp;Babajan Banaganapalli,&nbsp;Abdulrahman Mujalli,&nbsp;Nuha AlRayes,&nbsp;Sarah Almaghrabi,&nbsp;Majid Almansouri,&nbsp;Ahmed Sahly,&nbsp;Gada Ali Jadkarim,&nbsp;Md Zubbair Malik,&nbsp;Hussam Ibrahim Kutbi,&nbsp;Noor Ahmad Shaik,&nbsp;Eman Alefishat","doi":"10.1177/11779322231166214","DOIUrl":"https://doi.org/10.1177/11779322231166214","url":null,"abstract":"<p><p>The Parkinson disease (PD) is the second most common neurodegenerative disorder affecting the central nervous system and motor functions. The biological complexity of PD is yet to reveal potential targets for intervention or to slow the disease severity. Therefore, this study aimed to compare the fidelity of blood to substantia nigra (SN) tissue gene expression from PD patients to provide a systematic approach to predict role of the key genes of PD pathobiology. Differentially expressed genes (DEGs) from multiple microarray data sets of PD blood and SN tissue from GEO database are identified. Using the theoretical network approach and variety of bioinformatic tools, we prioritized the key genes from DEGs. A total of 540 and 1024 DEGs were identified in blood and SN tissue samples, respectively. Functional pathways closely related to PD such as ERK1 and ERK2 cascades, mitogen-activated protein kinase (MAPK) signaling, Wnt, nuclear factor-κB (NF-κB), and PI3K-Akt signaling were observed by enrichment analysis. Expression patterns of 13 DEGs were similar in both blood and SN tissues. Comprehensive network topological analysis and gene regulatory networks identified additional 10 DEGs functionally connected with molecular mechanisms of PD through the mammalian target of rapamycin (mTOR), autophagy, and AMP-activated protein kinase (AMPK) signaling pathways. Potential drug molecules were identified by chemical-protein network and drug prediction analysis. These potential candidates can be further validated in vitro/in vivo to be used as biomarkers and/or novel drug targets for the PD pathology and/or to arrest or delay the neurodegeneration over the years, respectively.</p>","PeriodicalId":9065,"journal":{"name":"Bioinformatics and Biology Insights","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/59/b3/10.1177_11779322231166214.PMC10155030.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10289663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of Novel C319T Variant of <i>PITX2</i> Gene 3'UTR Region With Reproductive Performance in Awassi Sheep.","authors":"Ahmed H Alkhammas,&nbsp;Tahreer M Al-Thuwaini,&nbsp;Mohammed Baqur S Al-Shuhaib,&nbsp;Neam M Khazaal","doi":"10.1177/11779322231179018","DOIUrl":"https://doi.org/10.1177/11779322231179018","url":null,"abstract":"<p><p>Several genes influence sheep's reproductive performance, among them the paired-like homeodomain transcription factor 2 (<i>PITX2</i>) gene. Thus, this study aimed to examine whether the variability within the <i>PITX2</i> gene is associated with the reproductive performance of Awassi ewes. A total of 123 single-progeny ewes and 109 twin ewes were used to extract genomic DNA. An amplicon of 4 sequence fragments from exons 2, 4, 5 (upstream portion), and 5 (downstream portion) of the <i>PITX2</i> gene was generated by polymerase chain reaction (PCR), 228, 304, 381, and 382 bp, respectively. Three genotypes of 382 bp amplicons were identified: CC, CT, and TT. Sequence analysis revealed a novel mutation in the CT genotype 319C > T. Statistical analysis revealed that single-nucleotide polymorphism (SNP) 319C > T was associated with reproductive performance. Single-nucleotide polymorphism 319C > T-carrying ewes had significantly (<i>P</i> ⩽ .01) lower litter sizes, twinning rates, lambing rates, and more days to lambing than those carrying CT and CC genotypes. Based on a logistic regression analysis, it was confirmed that the 319C > T SNP decreased litter size. Ewes with TT genotype produced fewer lambs than ewes with CT and CC genotypes. According to these results, the variant 319C> T SNP negatively affects the reproductive performance of Awassi sheep. Ewes carrying the 319C > T SNP have a lower litter size and are less prolific than those without the SNP.</p>","PeriodicalId":9065,"journal":{"name":"Bioinformatics and Biology Insights","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a1/43/10.1177_11779322231179018.PMC10259137.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9988197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indigenous Oral and Gut Phages Defeat the Deadly NDM-1 Superbug.","authors":"Pradeep Kumar Yadalam,&nbsp;Raghavendra Vamsi Anegundi,&nbsp;Ramya Ramadoss,&nbsp;M Saravanan,&nbsp;AshokKumar Veeramuthu,&nbsp;Artak Heboyan","doi":"10.1177/11779322231182767","DOIUrl":"https://doi.org/10.1177/11779322231182767","url":null,"abstract":"<p><strong>Aim: </strong>Antibiotics treat various diseases by targeting microorganisms by killing them or reducing their multiplication rate. New Delhi Metallo-beta-lactamase-1 (NDM-1) is produced by bacteria possessing the resistance gene blaNDM-1, the enzyme that makes bacteria resistant to beta-lactams. Bacteriophages, especially Lactococcus, have shown their ability to break down lactams. Hence, the current study computationally evaluated the binding potential of Lactococcus bacteriophages with NDM using Molecular docking and dynamics.</p><p><strong>Methods: </strong>Modelling of NDM I-TASSER for Main tail protein gp19 OS=Lactococcus phage LL-H or Lactobacillus delbrueckii subsp. lactis after downloading from UNIPROT ID- Q38344. Cluspro tool helps in Understanding cellular function and organization with protein-protein interactions. MD simulations(19) typically compute atom movements over time. Simulations were used to predict the ligand binding status in the physiological environment.</p><p><strong>Results: </strong>The best binding affinity score was found -1040.6 Kcal/mol compared to other docking scores. MD simulations show in RMSD values for target remains within 1.0 Angstrom, which is acceptable. The ligand-protein fit to receptor protein RMSD values of 2.752 fluctuates within 1.5 Angstrom after equilibration.</p><p><strong>Conclusions: </strong>Lactococcus bacteriophages showed a strong affinity to the NDM. Hence, this hypothesis, supported by evidence from a computational approach, will solve this life-threatening superbug problem.</p>","PeriodicalId":9065,"journal":{"name":"Bioinformatics and Biology Insights","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/14/aa/10.1177_11779322231182767.PMC10291530.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9729772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Inhibitor of DKK1/LRP6 Interactions Against the Alzheimer Disease: An Insilco Approach.","authors":"Manisha Prajapat,&nbsp;Harvinder Singh,&nbsp;Gajendra Chaudhary,&nbsp;Phulen Sarma,&nbsp;Gurjeet Kaur,&nbsp;Ajay Prakash Patel,&nbsp;Bikash Medhi","doi":"10.1177/11779322231183762","DOIUrl":"https://doi.org/10.1177/11779322231183762","url":null,"abstract":"<p><p>The activation of the Wnt signaling pathway is implicated in a neuroprotective mechanism against the Alzheimer disease. When this pathway is blocked, it activates GSK3 beta, leading to tau hyperphosphorylation and the apoptosis of neurons. Dickkopf-related protein 1 (DKK1) is a protein that competes with the Wnt ligand for the low-density lipoprotein receptor-related protein 6 (LRP6) receptor's binding, interrupting the Wnt-induced Fzd-Wnt-LRP6 complex. This counteracts Wnt's neuroprotective effect and contributes to the progression of the Alzheimer disease. The aim of this study was to use in silico approach to develop new agents that can combat the Alzheimer disease by targeting the interaction between DKK1 and LRP6. To achieve this, we conducted a virtual screening (Vsw) of the Asinex-CNS database library (n = 54 513) compounds against a generated grid in LRP6 protein. From this screening, we selected 6 compounds based on their docking score and performed molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations on the selected ligands. Next, we evaluated the Absorption, Distribution, Metabolism, and Excretion (ADME) results of the 6 screened compounds using the Quick prop module of Schrödinger. We then employed several computational techniques, including PCA (Principal Component Analysis), DCCM (Dynamic Cross-Correlation Map), molecular dynamics simulation, and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA)-based negative binding free energy (BFE) calculation, to further analyze the compounds. Our extensive computational analysis resulted in the identification of 3 potential hits, LAS 29757582, LAS 29984441, and LAS 29757942. These compounds were found to block the interaction of DKK1 with LRP6 (A and B interface) protein, and their potential as therapeutic agents was supported by negative BFE calculation. Therefore, these compounds show potential as possible therapeutic agents for treating the Alzheimer disease through targeting the interaction between DKK1 and LRP6.</p>","PeriodicalId":9065,"journal":{"name":"Bioinformatics and Biology Insights","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b4/e3/10.1177_11779322231183762.PMC10328054.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9799561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}