Investigating drug–target interactions in frontotemporal dementia using a network pharmacology approach

Abstract

Background Frontotemporal dementia (FTD) is the second most common type of dementia in individuals aged below 65 years with no current cure. Current treatment plan is the administration of multiple medications. This has the issue of causing adverse effects due to unintentional drug–drug interactions. Therefore, there exists an urgent need to propose a novel targeted therapy that can maximize the benefits of FTD-specific drugs while minimizing its associated adverse side effects. In this study, we implemented the concept of network pharmacology to understand the mechanism underlying FTD and highlight specific drug–gene and drug–drug interactions that can provide an interesting perspective in proposing a targeted therapy against FTD. Results We constructed protein–protein, drug–gene and drug–drug interaction networks to identify highly connected nodes and analysed their importance in associated enriched pathways. We also performed a historeceptomics analysis to determine tissue-specific drug interactions. Through this study, we were able to shed light on the APP gene involved in FTD. The APP gene which was previously known to cause FTD cases in a small percentage is now being extensively studied owing to new reports claiming its participation in neurodegeneration. Our findings strengthen this hypothesis as the APP gene was found to have the highest node degree and betweenness centrality in our protein–protein interaction network and formed an essential hub node between disease susceptibility genes and neuroactive ligand–receptors. Our findings also support the study of FTD being presented as a case of substance abuse. Our protein–protein interaction network highlights the target genes common to substance abuse (nicotine, morphine and cocaine addiction) and neuroactive ligand–receptor interaction pathways, therefore validating the cognitive impairment caused by substance abuse as a symptom of FTD. Conclusions Our study abandons the one-target one-drug approach and uses networks to define the disease mechanism underlying FTD. We were able to highlight important genes and pathways involved in FTD and analyse their relation with existing drugs that can provide an insight into effective medication management.

Drug Discovery and Development Targeting Dementia

“…Moreover, many biological targets and signaling pathways are involved in the pathology of dementia. There is substantial literature that focuses on drug targets for AD [ 67 , 68 , 69 , 70 , 71 , 72 , 73 ], LBD [ 74 , 75 , 76 , 77 ], FTD [ 78 , 79 , 80 , 81 ], and VD [ 82 , 83 , 84 ]. As a result of a better understanding of the biochemical regulation of the mechanisms leading to dementia, new molecular targets have been introduced into clinical trials ( Table 3 ).…”