Comparative Metabolic Pathways Analysis and Subtractive Genomics Profiling to Prioritize Potential Drug Targets Against Streptococcus pneumoniae

Khan, Kanwal; Jalal, Khurshid; Khan, Ajmal; Al‐Harrasi, Ahmed; Uddin, Reaz

doi:10.3389/fmicb.2021.796363

Cited by 18 publications

(14 citation statements)

References 56 publications

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“…It has been reported that cytoplasmic proteins are an excellent therapeutic target and may be readily targeted with drugs [ 29 ]. Additionally, ~70 percent of FDA-approved medications are claimed to target enzymatic proteins because of their substantial participation in numerous pathways.…”

Section: Resultsmentioning

confidence: 99%

Integrated Bioinformatics-Based Subtractive Genomics Approach to Decipher the Therapeutic Drug Target and Its Possible Intervention against Brucellosis

et al. 2022

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Brucella suis, one of the causative agents of brucellosis, is Gram-negative intracellular bacteria that may be found all over the globe and it is a significant facultative zoonotic pathogen found in livestock. It may adapt to a phagocytic environment, reproduce, and develop resistance to harmful environments inside host cells, which is a crucial part of the Brucella life cycle making it a worldwide menace. The molecular underpinnings of Brucella pathogenicity have been substantially elucidated due to comprehensive methods such as proteomics. Therefore, we aim to explore the complete Brucella suis proteome to prioritize the novel proteins as drug targets via subtractive proteo-genomics analysis, an effort to conjecture the existence of distinct pathways in the development of brucellosis. Consequently, 38 unique metabolic pathways having 503 proteins were observed while among these 503 proteins, the non-homologs (n = 421), essential (n = 350), drug-like (n = 114), virulence (n = 45), resistance (n = 42), and unique to pathogen proteins were retrieved from Brucella suis. The applied subsequent hierarchical shortlisting resulted in a protein, i.e., isocitrate lyase, that may act as potential drug target, which was finalized after the extensive literature survey. The interacting partners for these shortlisted drug targets were identified through the STRING database. Moreover, structure-based studies were also performed on isocitrate lyase to further analyze its function. For that purpose, ~18,000 ZINC compounds were screened to identify new potent drug candidates against isocitrate lyase for brucellosis. It resulted in the shortlisting of six compounds, i.e., ZINC95543764, ZINC02688148, ZINC20115475, ZINC04232055, ZINC04231816, and ZINC04259566 that potentially inhibit isocitrate lyase. However, the ADMET profiling showed that all compounds fulfill ADMET properties except for ZINC20115475 showing positive Ames activity; whereas, ZINC02688148, ZINC04259566, ZINC04232055, and ZINC04231816 showed hepatoxicity while all compounds were observed to have no skin sensitization. In light of these parameters, we recommend ZINC95543764 compound for further experimental studies. According to the present research, which uses subtractive genomics, proteins that might serve as therapeutic targets and potential lead options for eradicating brucellosis have been narrowed down.

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Section: Resultsmentioning

confidence: 99%

Integrated Bioinformatics-Based Subtractive Genomics Approach to Decipher the Therapeutic Drug Target and Its Possible Intervention against Brucellosis

et al. 2022

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“…It has been reported that cytoplasmic proteins are an excellent therapeutic target and may be readily targeted with drugs [ 56 ]. Additionally, ~70 percent FDA approved medications are claimed to target enzymatic proteins because of their substantial participation in numerous pathways.…”

Section: Resultsmentioning

confidence: 99%

Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum

Alturki

Mashraqi

Jalal

et al. 2022

Cancers

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

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“…Proteins participating in unique pathways may exhibit homology with human and host citrus plant [52].…”

Section: Discussionmentioning

confidence: 99%

Subtractive Genome mining in Xanthomonas citri pv. Citri strain 306 for identifying novel drug target proteins coupled with in-depth protein-protein interaction and coevolution analysis - A leap towards prospective drug design

Mahato,

Mandal,

Chatterjee

et al. 2024

Preprint

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Citrus canker (CC) poses a serious threat to a highly significant citrus fruit crop, this disease caused by one of the most destructive bacterial plant pathogens Xanthomonas citri pv. citri. Bacterial plant diseases cause substantial global losses in crop production. Reducing crop yield losses is necessary to meet growing global food demands with a rising population. High rates of antibiotic resistance to conventional pesticides and antibiotics among Xanthomonas citri pv. citri (XCC) strains the effectiveness of current control methods is diminishing, have rendered treatment management more challenging and highlighted the need for novel therapeutic targets or new approaches to combat the rising antimicrobial resistance trend. Utilizing OMICS data offers an appealing alternative to experimental methods, propelling drug discovery and reducing the risk of later-stage drug failures. Using an innovative hierarchical computational method, the goal of this present study was to identify and characterize potential drug targets against the pathogen XCC strain 306. The study involved retrieving the XAC proteome from the UniProt database, eliminating paralogous proteins using CD-HIT (80% identity cutoff), and selecting nonhomologous proteins through BLASTp (e-value < 0.005). Essential proteins were identified using BLAST against the DEG (e-value cutoff 0.00001). Subsequent analyses included metabolic pathway assessment, subcellular localization prediction, and druggability analysis. Protein network analysis, coevolution analysis (CoeViz server), protein active site identification (CastP 3.0), and centrality betweenness graph plotting (ProsNex) were performed. In conclusion, this study identified eight drug targets (GlmU, CheA, RmlD, GspE, FleQ, RpoN, Shk, SecB), highlighting RpoN, FleQ, and SecB as unprecedented targets for XCC. These findings may contribute to the development of novel antimicrobial agents in the future that can efficiently control citrus canker disease.

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Comparative Metabolic Pathways Analysis and Subtractive Genomics Profiling to Prioritize Potential Drug Targets Against Streptococcus pneumoniae

Abstract: Graphical Abstract

Cited by 18 publications

References 56 publications

Integrated Bioinformatics-Based Subtractive Genomics Approach to Decipher the Therapeutic Drug Target and Its Possible Intervention against Brucellosis

Integrated Bioinformatics-Based Subtractive Genomics Approach to Decipher the Therapeutic Drug Target and Its Possible Intervention against Brucellosis

Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum

Subtractive Genome mining in Xanthomonas citri pv. Citri strain 306 for identifying novel drug target proteins coupled with in-depth protein-protein interaction and coevolution analysis - A leap towards prospective drug design

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