Multitarget Potential Drug Candidates for High-Grade Gliomas Identified by Multiple Reaction Monitoring Coupled with...

Area of Science:

• Neuro-oncology
• Computational Biology
• Pharmacology

Background:

• High-grade gliomas (HGGs) are aggressive brain tumors with limited treatment options.
• Proteomics and clinical research have identified biomarkers but few effective drugs.
• There is a critical need for novel therapeutic targets and drug candidates for HGGs.

Purpose of the Study:

• To identify potential drug candidates for high-grade gliomas using a multi-pronged approach.
• To discover multitarget-directed ligands for HGGs through drug repurposing.
• To evaluate the efficacy of identified drug candidates in preclinical models.

Main Methods:

• Targeted proteomics using multiple reaction monitoring (MRM) on differentially expressed proteins.
• In silico molecular docking and simulation-based drug repurposing with FDA-approved drugs.
• Drug-likeness assessment (SwissADME), molecular dynamics, and cell toxicity assays.

Main Results:

• Identified five potential drug candidates, including Pazopanib, Icotinib, Entrectinib, Regorafenib, and Cabozantinib.
• Pazopanib demonstrated strong binding affinities and was selected for further simulation and toxicity studies.
• Pazopanib combined with Temozolomide significantly enhanced cytotoxicity and inhibited proliferation in HGG cell lines.

Conclusions:

• This study presents a novel integrated strategy combining MRM, molecular docking, and simulation for HGG drug discovery.
• Pazopanib is a promising candidate, particularly in combination therapy, warranting further clinical investigation.
• The methodology offers innovative avenues for developing treatments for aggressive cancers with poor prognoses.