A TRANSCRIPTOMICS DRIVEN DRUG REPURPOSING STRATEGY TO IDENTIFY NOVEL THERAPEUTIC TARGETS ASSOCIATED WITH TREATMENT RESPONSES IN MULTIPLE SCLEROSIS
Author(s)
Nayana M. Ramanujam, PharmD, Kshreeraja S. Satish, PharmD, Ganesan Rajalekshmi Saraswathy, PhD.
M. S. Ramaiah University Of Applied Sciences, Bangalore, India.
M. S. Ramaiah University Of Applied Sciences, Bangalore, India.
OBJECTIVES: Multiple Sclerosis (MS) is an autoimmune neurodegenerative disorder, and despite dimethyl fumarate being an established disease-modifying therapy, treatment responses vary considerably among patients, and biomarkers distinguishing these responses remain poorly characterized. This study aims to identify treatment response-associated targets and prioritize repurposable drugs to improve treatment outcomes using an integrative transcriptomic, network pharmacology, and structure-based drug repurposing approach.
METHODS: Differential gene expression analysis was performed using GEO2R on transcriptomic dataset GSE235357, comprising 30 samples of peripheral blood mononuclear cells from Responders (R), Non-Responders (NR), and Healthy Controls (C). Differentially Expressed Genes (DEGs) for R vs C and NR vs C were shortlisted based on adjusted p < 0.05 and log2FC > 1.5. Next, DEGs unique to R and NR groups were identified using a Venn diagram and Protein-protein interaction (PPI) networks were constructed using STRING. Genes with a node degree of >1 were evaluated for biological relevance and druggability. Targets with contradictory literature evidence or lacking known compounds were excluded, and a target-specific library was curated from DrugBank. The drug libraries were screened using the Schrödinger Drug Discovery Suite and evaluated for binding affinity.
RESULTS: A total of 78 and 71 significant DEGs were identified in the R vs C and NR vs C comparisons, respectively. Of these, FABP4 was shortlisted as a target owing to its role in MS progression. Given that it was upregulated in NRs, we aimed to unearth inhibitors by using known inhibitors, (S)-RP-6306 and Osimertinib, as reference compounds to develop a drug library with structurally similar drugs. Molecular docking identified Droperidol and Camptothecin as the top candidates, with docking scores of −6.477 and −5.975 kcal/mol, respectively.
CONCLUSIONS: This integrative workflow identified FABP4 as a potential therapeutic target and highlighted Droperidol and Camptothecin as promising repurposable candidates for Multiple Sclerosis, warranting further experimental and clinical validation.
METHODS: Differential gene expression analysis was performed using GEO2R on transcriptomic dataset GSE235357, comprising 30 samples of peripheral blood mononuclear cells from Responders (R), Non-Responders (NR), and Healthy Controls (C). Differentially Expressed Genes (DEGs) for R vs C and NR vs C were shortlisted based on adjusted p < 0.05 and log2FC > 1.5. Next, DEGs unique to R and NR groups were identified using a Venn diagram and Protein-protein interaction (PPI) networks were constructed using STRING. Genes with a node degree of >1 were evaluated for biological relevance and druggability. Targets with contradictory literature evidence or lacking known compounds were excluded, and a target-specific library was curated from DrugBank. The drug libraries were screened using the Schrödinger Drug Discovery Suite and evaluated for binding affinity.
RESULTS: A total of 78 and 71 significant DEGs were identified in the R vs C and NR vs C comparisons, respectively. Of these, FABP4 was shortlisted as a target owing to its role in MS progression. Given that it was upregulated in NRs, we aimed to unearth inhibitors by using known inhibitors, (S)-RP-6306 and Osimertinib, as reference compounds to develop a drug library with structurally similar drugs. Molecular docking identified Droperidol and Camptothecin as the top candidates, with docking scores of −6.477 and −5.975 kcal/mol, respectively.
CONCLUSIONS: This integrative workflow identified FABP4 as a potential therapeutic target and highlighted Droperidol and Camptothecin as promising repurposable candidates for Multiple Sclerosis, warranting further experimental and clinical validation.
Conference/Value in Health Info
2026-11, ISPOR Europe 2026, Vienna, Austria
Value in Health, Volume 29, Issue 12S
Code
SA47
Topic
Clinical Outcomes, Methodological & Statistical Research, Study Approaches
Disease
Neurological Disorders, No Additional Disease & Conditions/Specialized Treatment Areas, Personalized & Precision Medicine, Systemic Disorders/Conditions (Anesthesia, Auto-Immune Disorders (n.e.c.), Hematological Disorders (non-oncologic), Pain)