Exploring a Potential Cerebral Hemorrhage Signal Linked to Selumetinib: Insights From Bioinformatics and Gene Docking Studies
Author(s)
Bhumika M, Jr., MPH1, Eswaran Maheswari, Sr., PhD2.
1Pharmacy Practice, M S Ramaiah University of Applied Sciences, Bangalore, India, 2Pharmacy Practice, M S Ramaiah University Of Applied Sciences, Bangalore, India.
1Pharmacy Practice, M S Ramaiah University of Applied Sciences, Bangalore, India, 2Pharmacy Practice, M S Ramaiah University Of Applied Sciences, Bangalore, India.
OBJECTIVES: Selumetinib, a selective MEK1/2 inhibitor, is approved for treating neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas and various malignancies. Post-marketing surveillance is essential to uncover adverse drug reactions (ADRs) not evident in clinical trials. This study aimed to identify a potential signal for selumetinib using the U.S. FDA Adverse Event Reporting System (FAERS), combined with bioinformatics and molecular docking analyses
METHODS: FAERS data were mined for selumetinib-related ADRs using OpenVigil 2.1. Disproportionality analysis was performed with signal thresholds defined as Proportional Reporting Ratio (PRR) >2, Reporting Odds Ratio (ROR) >2, drug events >2 and chi square >4 with a lower bound of 95% confidence interval >1. Genes associated with hemorrhagic events were identified through KEGG and HUGE Navigator, and cross-validated using STITCH and STRING databases. Molecular docking between selumetinib and identified target proteins was carried out using the docking software.
RESULTS: Out of 30,668,520 FAERS reports, 14 cases of cerebral hemorrhage associated with selumetinib were identified. Selumetinib was approved by the Food and Drug Administration on April 10, 2020 for pediatric patients. Disproportionality analysis yielded a PRR of 4.996 and ROR of 5.017, chi square value of 9.10 indicating a strong pharmacovigilance signal. Protein-protein interaction mapping highlighted RAC1 (PDB ID: 5N6O), APOE (PDB ID 8G2O) and ITGAV (PDB ID 9CZ7) as a key target. Molecular docking demonstrated a binding affinity of -4.08, -3.24 and -3.07 kcal/mol between selumetinib and RAC1, APOE and ITGAV respectively supporting a plausible mechanistic link.
CONCLUSIONS: This study reveals a statistically significant signal associating selumetinib with cerebral hemorrhage. The observed interaction with RAC1 through docking analysis suggests a potential molecular mechanism. These findings warrant further investigation through pharmacogenomic and epidemiological studies to validate the signal and understand the pathophysiology involved.
METHODS: FAERS data were mined for selumetinib-related ADRs using OpenVigil 2.1. Disproportionality analysis was performed with signal thresholds defined as Proportional Reporting Ratio (PRR) >2, Reporting Odds Ratio (ROR) >2, drug events >2 and chi square >4 with a lower bound of 95% confidence interval >1. Genes associated with hemorrhagic events were identified through KEGG and HUGE Navigator, and cross-validated using STITCH and STRING databases. Molecular docking between selumetinib and identified target proteins was carried out using the docking software.
RESULTS: Out of 30,668,520 FAERS reports, 14 cases of cerebral hemorrhage associated with selumetinib were identified. Selumetinib was approved by the Food and Drug Administration on April 10, 2020 for pediatric patients. Disproportionality analysis yielded a PRR of 4.996 and ROR of 5.017, chi square value of 9.10 indicating a strong pharmacovigilance signal. Protein-protein interaction mapping highlighted RAC1 (PDB ID: 5N6O), APOE (PDB ID 8G2O) and ITGAV (PDB ID 9CZ7) as a key target. Molecular docking demonstrated a binding affinity of -4.08, -3.24 and -3.07 kcal/mol between selumetinib and RAC1, APOE and ITGAV respectively supporting a plausible mechanistic link.
CONCLUSIONS: This study reveals a statistically significant signal associating selumetinib with cerebral hemorrhage. The observed interaction with RAC1 through docking analysis suggests a potential molecular mechanism. These findings warrant further investigation through pharmacogenomic and epidemiological studies to validate the signal and understand the pathophysiology involved.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
RWD83
Topic
Clinical Outcomes, Epidemiology & Public Health, Real World Data & Information Systems
Topic Subcategory
Distributed Data & Research Networks
Disease
Neurological Disorders