Drug Repurposing for AML: Structure-Based Virtual Screening and Molecular Simulations of FDA-Approved Compounds with...

Area of Science:

• Oncology
• Pharmacology
• Computational Biology

Background:

• Acute myeloid leukemia (AML) is a complex cancer with poor outcomes due to resistance to therapies.
• Current treatments targeting specific pathways like epigenetic modifiers (LSD1), apoptosis regulators (BCL-2), and metabolic enzymes (IDH1) show limited efficacy.
• Compensatory signaling and clonal evolution in AML necessitate novel therapeutic strategies.

Purpose of the Study:

• To identify FDA-approved compounds capable of simultaneously targeting key epigenetic, apoptotic, and metabolic pathways in AML.
• To explore a polypharmacology approach for AML treatment using repurposed drugs.
• To investigate potential multitarget agents for overcoming therapeutic resistance in AML.

Main Methods:

• Structure-based virtual screening of 3957 FDA-approved molecules against LSD1, BCL-2, and mutant IDH1 (R132H).
• In silico evaluation of top hits using ADMET prediction for pharmacokinetic and safety profiling.
• Molecular dynamics (MD) simulations to assess ligand-protein complex stability over 100 ns.

Main Results:

• Three compounds (DB16703, DB08512, DB16047) demonstrated high binding affinity across all three AML targets.
• These compounds exhibited favorable predicted pharmacokinetic and safety profiles.
• MD simulations confirmed stable interactions between the compounds and their target proteins.

Conclusions:

• Computational screening identified promising repurposed drugs for a polypharmacology strategy in AML.
• The identified compounds could potentially modulate epigenetic, apoptotic, and metabolic pathways simultaneously.
• Further preclinical validation is required to confirm the efficacy of Belumosudil, DB08512, and Elraglusib in AML models.