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. 2024 Jan 9;25(1):43.
doi: 10.1186/s12864-023-09913-1.

Identifying patterns to uncover the importance of biological pathways on known drug repurposing scenarios

Belén Otero-Carrasco  1   2 , Esther Ugarte Carro  1 , Lucía Prieto-Santamaría  1   2 , Marina Diaz Uzquiano  1 , Juan Pedro Caraça-Valente Hernández  2 , Alejandro Rodríguez-González  3   4
Affiliations

Identifying patterns to uncover the importance of biological pathways on known drug repurposing scenarios

Belén Otero-Carrasco et al. BMC Genomics. .

Abstract

Background: Drug repurposing plays a significant role in providing effective treatments for certain diseases faster and more cost-effectively. Successful repurposing cases are mostly supported by a classical paradigm that stems from de novo drug development. This paradigm is based on the "one-drug-one-target-one-disease" idea. It consists of designing drugs specifically for a single disease and its drug's gene target. In this article, we investigated the use of biological pathways as potential elements to achieve effective drug repurposing.

Methods: Considering a total of 4214 successful cases of drug repurposing, we identified cases in which biological pathways serve as the underlying basis for successful repurposing, referred to as DREBIOP. Once the repurposing cases based on pathways were identified, we studied their inherent patterns by considering the different biological elements associated with this dataset, as well as the pathways involved in these cases. Furthermore, we obtained gene-disease association values to demonstrate the diminished significance of the drug's gene target in these repurposing cases. To achieve this, we compared the values obtained for the DREBIOP set with the overall association values found in DISNET, as well as with the drug's target gene (DREGE) based repurposing cases using the Mann-Whitney U Test.

Results: A collection of drug repurposing cases, known as DREBIOP, was identified as a result. DREBIOP cases exhibit distinct characteristics compared with DREGE cases. Notably, DREBIOP cases are associated with a higher number of biological pathways, with Vitamin D Metabolism and ACE inhibitors being the most prominent pathways. Additionally, it was observed that the association values of GDAs in DREBIOP cases were significantly lower than those in DREGE cases (p-value < 0.05).

Conclusions: Biological pathways assume a pivotal role in drug repurposing cases. This investigation successfully revealed patterns that distinguish drug repurposing instances associated with biological pathways. These identified patterns can be applied to any known repurposing case, enabling the detection of pathway-based repurposing scenarios or the classical paradigm.

Keywords: Computational biology; DISNET knowledge; Data-driven methodology; Drug repurposing; Pathway-based.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Description of the two types of triples and a real case for each of them. In the left part, we can observe the description of the components that constitute the two different types of drug repurposing triples A) DREBIOP B) DREGE. On the right part, we can observe a real case of repositioning found in our results for both A) DREBIOP and B) DREGE
Fig. 2
Fig. 2
Summary of the different analyses used in this research to determine the importance of biological pathways in drug repurposing
Fig. 3
Fig. 3
Methodology applied to obtain patterns based on the GDAs values. In the first step, the GDA value of DREBIOP, DREGE and DISNET is calculated. Then, a statistical comparison is carried out by means of a Mann-Whitney U Test between the DREBIOP repositioning cases and the DREGE cases, and between DREBIOP and DISNET
Fig. 4
Fig. 4
Summary of DREBIOP, DREGE and DISNET datasets GDA score distributions. GDA score distributions in the DREBIOP, DREGE and DISNET datasets as well as the statistical results obtained by performing the Mann-Whitney U-test to compare the GDA values between the cases represented. P-value annotation legend: ns: 5.00 × 10-2 < p < = 1, *: 1.00 × 10−2 < p < = 5.00 × 10−2
Fig. 5
Fig. 5
Representation of a real DREBIOP repurposing triple through all the results obtained for the different proposed strategies
See this image and copyright information in PMC

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