Genomic and computational-aided integrative drug repositioning strategy for EGFR and ROS1 mutated NSCLC
Language English Country Netherlands Media print-electronic
Document type Journal Article
PubMed
39029228
DOI
10.1016/j.intimp.2024.112682
PII: S1567-5769(24)01203-7
Knihovny.cz E-resources
- Keywords
- Drug repositioning, Drug resistance, Lung Cancer, Molecular Dynamics Simulation, Transcriptome analysis,
- MeSH
- ErbB Receptors * genetics antagonists & inhibitors MeSH
- Genomics methods MeSH
- Protein Kinase Inhibitors pharmacology therapeutic use MeSH
- Humans MeSH
- Mutation * MeSH
- Lung Neoplasms * genetics drug therapy MeSH
- Carcinoma, Non-Small-Cell Lung * drug therapy genetics MeSH
- Drug Repositioning * MeSH
- Antineoplastic Agents * pharmacology therapeutic use MeSH
- Proto-Oncogene Proteins * genetics MeSH
- Molecular Docking Simulation MeSH
- Protein-Tyrosine Kinases * genetics antagonists & inhibitors MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- EGFR protein, human MeSH Browser
- ErbB Receptors * MeSH
- Protein Kinase Inhibitors MeSH
- Antineoplastic Agents * MeSH
- Proto-Oncogene Proteins * MeSH
- ROS1 protein, human MeSH Browser
- Protein-Tyrosine Kinases * MeSH
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.
Department of Biochemistry Dr Ram Manohar Lohia Avadh University Ayodhya Uttar Pradesh India
School of Life Sciences Gwangju Institute of Science and Technology Gwangju Republic of Korea
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