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

SIMPLE SUMMARY: More and more studies are suggesting the role of microbes in several diseases in addition to the germline and environmental factors. F. nucleatum is recently being associated with colorectal cancer and here, we aimed to identify important drug targets from the core genome of colorect...

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Autores principales: Alturki, Norah A., Mashraqi, Mutaib M., Jalal, Khurshid, Khan, Kanwal, Basharat, Zarrin, Alzamami, Ahmad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9777469/
https://www.ncbi.nlm.nih.gov/pubmed/36551744
http://dx.doi.org/10.3390/cancers14246260
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author Alturki, Norah A.
Mashraqi, Mutaib M.
Jalal, Khurshid
Khan, Kanwal
Basharat, Zarrin
Alzamami, Ahmad
author_facet Alturki, Norah A.
Mashraqi, Mutaib M.
Jalal, Khurshid
Khan, Kanwal
Basharat, Zarrin
Alzamami, Ahmad
author_sort Alturki, Norah A.
collection PubMed
description SIMPLE SUMMARY: More and more studies are suggesting the role of microbes in several diseases in addition to the germline and environmental factors. F. nucleatum is recently being associated with colorectal cancer and here, we aimed to identify important drug targets from the core genome of colorectal cancer associated F. nucleatum through bioinformatics approach. We used one drug target for further analysis and obtained natural product inhibitors against it. Finally, we validated inhibition stability through dynamics simulation approach. We are hopeful that this study could benefit researchers working on colorectal cancer, its microbiome and cure. ABSTRACT: 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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spelling pubmed-97774692022-12-23 Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum Alturki, Norah A. Mashraqi, Mutaib M. Jalal, Khurshid Khan, Kanwal Basharat, Zarrin Alzamami, Ahmad Cancers (Basel) Article SIMPLE SUMMARY: More and more studies are suggesting the role of microbes in several diseases in addition to the germline and environmental factors. F. nucleatum is recently being associated with colorectal cancer and here, we aimed to identify important drug targets from the core genome of colorectal cancer associated F. nucleatum through bioinformatics approach. We used one drug target for further analysis and obtained natural product inhibitors against it. Finally, we validated inhibition stability through dynamics simulation approach. We are hopeful that this study could benefit researchers working on colorectal cancer, its microbiome and cure. ABSTRACT: 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. MDPI 2022-12-19 /pmc/articles/PMC9777469/ /pubmed/36551744 http://dx.doi.org/10.3390/cancers14246260 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Alturki, Norah A.
Mashraqi, Mutaib M.
Jalal, Khurshid
Khan, Kanwal
Basharat, Zarrin
Alzamami, Ahmad
Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum
title Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum
title_full Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum
title_fullStr Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum
title_full_unstemmed Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum
title_short Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum
title_sort therapeutic target identification and inhibitor screening against riboflavin synthase of colorectal cancer associated fusobacterium nucleatum
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9777469/
https://www.ncbi.nlm.nih.gov/pubmed/36551744
http://dx.doi.org/10.3390/cancers14246260
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