Skolariki Konstantina, Vlamos Panagiotis
Bioinformatics and Human Electrophysiology Laboratory, Department of Informatics, Ionian University, Corfu, Greece.
Front Comput Neurosci. 2024 Jan 11;17:1307523. doi: 10.3389/fncom.2023.1307523. eCollection 2023.
Post-Traumatic Stress Disorder (PTSD) is a mental disorder that can develop after experiencing traumatic events. The aim of this work is to explore the role of genes and genetic variations in the development and progression of PTSD.
Through three methodological approaches, 122 genes and 184 Single Nucleotide Polymorphisms (SNPs) associated with PTSD were compiled into a single gene repository for PTSD. Using PharmGKB and DrugTargetor, 323 drug candidates were identified to target these 122 genes. The top 17 drug candidates were selected based on the statistical significance of the genetic associations, and their promiscuity (number of associated genestargets) and were further assessed for their suitability in terms of bioavailability and drug-like characteristics. Through functional analysis, insights were gained into the biological processes, cellular components, and molecular functions involved in PTSD. This formed the foundation for the next aspect of this study which was to propose an efficient treatment for PTSD by exploring drug repurposing methods.
The main aim was to identify the drugs with the most favorable profile that can be used as a pharmacological approach for PTSD treatment. More in particular, according to the genetic variations present in each individual, the relevant biological pathway can be identified, and the drug candidate proposed will specifically target said pathway, accounting for the personalized aspect of this work. The results showed that the drugs used as off-label treatment for PTSD have favorable pharmacokinetic profiles and the potential drug candidates that arose from DrugTargetor were not very promising. Clozapine showed a promising pharmacokinetic profile and has been linked with decreased psychiatric symptoms. Ambrucin also showed a promising pharmacokinetic profile but has been mostly linked with cancer treatment.
创伤后应激障碍（PTSD）是一种在经历创伤性事件后可能出现的精神障碍。本研究的目的是探讨基因和基因变异在创伤后应激障碍发生和发展中的作用。
通过三种方法，将与创伤后应激障碍相关的122个基因和184个单核苷酸多态性（SNP）整合到一个创伤后应激障碍单基因库中。使用PharmGKB和DrugTargetor，确定了323种针对这122个基因的候选药物。根据基因关联的统计显著性、混杂性（相关基因-靶点的数量）选择了前17种候选药物，并进一步评估了它们在生物利用度和类药物特性方面的适用性。通过功能分析，深入了解了创伤后应激障碍所涉及的生物学过程、细胞成分和分子功能。这为研究的下一个方面奠定了基础，即通过探索药物再利用方法为创伤后应激障碍提出有效的治疗方案。
主要目的是确定具有最有利特征的药物，可作为创伤后应激障碍治疗的药理学方法。更具体地说，根据每个个体存在的基因变异，可以确定相关的生物学途径，所提出的候选药物将特异性地靶向该途径，这体现了本研究的个性化特点。结果表明，用于创伤后应激障碍标签外治疗的药物具有良好的药代动力学特征，而DrugTargetor产生的潜在候选药物前景不太乐观。氯氮平显示出有前景的药代动力学特征，并且与精神症状减轻有关。氨甲环酸也显示出有前景的药代动力学特征，但大多与癌症治疗有关。
