Genomic and computational-aided integrative drug repositioning strategy for EGFR and ROS1 mutated NSCLC

•Genome analysis of 476 LUSC samples reveals potential mutations within EGFR and ROS1.•Over 2083 FDA drugs were screened against eight NSCLC mutants by virtual screening.•Ledipasvir (>8.8 kcal/mol) identified as common drug for NSCLC mutants by docking.•MD simulation and MMGBSA supports eights as...

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Bibliographic Details
Published in:International immunopharmacology 2024-09, Vol.139, p.112682, Article 112682
Main Authors: Tripathi, Varsha, Khare, Aishwarya, Shukla, Divyanshi, Bharadwaj, Shiv, Kirtipal, Nikhil, Ranjan, Vandana
Format: Article
Language:English
Subjects:
Drug repositioning
Drug resistance
Lung Cancer
Molecular Dynamics Simulation
Transcriptome analysis
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Summary:•Genome analysis of 476 LUSC samples reveals potential mutations within EGFR and ROS1.•Over 2083 FDA drugs were screened against eight NSCLC mutants by virtual screening.•Ledipasvir (>8.8 kcal/mol) identified as common drug for NSCLC mutants by docking.•MD simulation and MMGBSA supports eights as potential drugs for NSCLC mutants. Non–small cell lung cancer (NSCLC) has been marked as the major cause of death in lung cancer patients. Due to tumor heterogeneity, mutation burden, and emerging resistance against the available therapies in NSCLC, it has been posing potential challenges in the therapy development. Hence, identification of cancer-driving mutations and their effective inhibition have been advocated as a potential approach in NSCLC treatment. Thereof, this study aims to employ the genomic and computational-aided integrative drug repositioning strategy to identify the potential mutations in the selected molecular targets and repurpose FDA-approved drugs against them. Accordingly, molecular targets and their mutations, i.e., EGFR (V843L, L858R, L861Q, and P1019L) and ROS1 (G1969E, F2046Y, Y2092C, and V2144I), were identified based on TCGA dataset analysis. Following, virtual screening and redocking analysis, Elbasvir, Ledipasvir, and Lomitapide drugs for EGFR mutants (>−10.8 kcal/mol) while Indinavir, Ledipasvir, Lomitapide, Monteleukast, and Isavuconazonium for ROS1 mutants (>−8.8 kcal/mol) were found as putative inhibitors. Furthermore, classical molecular dynamics simulation and endpoint binding energy calculation support the considerable stability of the selected docked complexes aided by substantial hydrogen bonding and hydrophobic interactions in comparison to the respective control complexes. Conclusively, the repositioned FDA-approved drugs might be beneficial alone or in synergy to overcome acquired resistance to EGFR and ROS1-positive lung cancers.
ISSN:1567-5769
1878-1705
1878-1705
DOI:10.1016/j.intimp.2024.112682