CONTRABASS: exploiting flux constraints in genome-scale models for the detection of vulnerabilities

Oarga, Alexandru (Universidad de Zaragoza) ; Bannerman, Bridget P ; Júlvez, Jorge (Universidad de Zaragoza)

Resumen: Motivation: Despite the fact that antimicrobial resistance is an increasing health concern, the pace of production of new drugs is slow due to the high cost and uncertain success of the process. The development of high-throughput technologies has allowed the integration of biological data into detailed genome-scale models of multiple organisms. Such models can be exploited by means of computational methods to identify system vulnerabilities such as chokepoint reactions and essential reactions. These vulnerabilities are appealing drug targets that can lead to novel drug developments. However, the current approach to compute these vulnerabilities is only based on topological data and ignores the dynamic information of the model. This can lead to misidentified drug targets.
Results: This work computes flux constraints that are consistent with a certain growth rate of the modelled organism, and integrates the computed flux constraints into the model to improve the detection of vulnerabilities. By exploiting these flux constraints, we are able to obtain a directionality of the reactions of metabolism consistent with a given growth rate of the model, and consequently, a more realistic detection of vulnerabilities can be performed. Several sets of reactions that are system vulnerabilities are defined and the relationships among them are studied. The approach for the detection of these vulnerabilities has been implemented in the Python tool CONTRABASS. Such tool, for which an online web server has also been implemented, computes flux constraints and generates a report with the detected vulnerabilities.

Idioma: Inglés

DOI: 10.1093/bioinformatics/btad053

Año: 2023

Publicado en: Bioinformatics 39, 2 (2023), [7 pp.]
ISSN: 1367-4803

Factor impacto JCR: 4.4 (2023)

Categ. JCR: BIOCHEMICAL RESEARCH METHODS rank: 11 / 85 = 0.129 (2023) - Q1 - T1
Categ. JCR: MATHEMATICAL & COMPUTATIONAL BIOLOGY rank: 7 / 66 = 0.106 (2023) - Q1 - T1
Categ. JCR: BIOTECHNOLOGY & APPLIED MICROBIOLOGY rank: 38 / 174 = 0.218 (2023) - Q1 - T1

Factor impacto CITESCORE: 11.2 - Computer Science Applications (Q1) - Biochemistry (Q1) - Molecular Biology (Q1) - Statistics and Probability (Q1) - Computational Theory and Mathematics (Q1) - Computational Mathematics (Q1)

Factor impacto SCIMAGO: 2.574 - Biochemistry (Q1) - Computational Mathematics (Q1) - Statistics and Probability (Q1) - Computer Science Applications (Q1) - Molecular Biology (Q1) - Computational Theory and Mathematics (Q1)

Financiación: info:eu-repo/grantAgreement/EUR/AEI/TED2021-130449B-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2020-113969RB-I00

Tipo y forma: Article (Published version)

Área (Departamento): Área Ingen.Sistemas y Automát. (Dpto. Informát.Ingenie.Sistms.)
Área (Departamento): Área Lenguajes y Sistemas Inf. (Dpto. Informát.Ingenie.Sistms.)