Targeting the Autophagy Specific Lipid Kinase VPS34 for Cancer Treatment: An Integrative Repurposing Strategy

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• Autophagy plays a crucial role in cancer treatment response.
• Targeting early-stage autophagy with novel inhibitors is a promising therapeutic strategy.
• Vacuolar protein sorting 34 (VPS34) is a key enzyme in autophagy initiation.

Purpose of the Study:

• To identify novel antagonists of VPS34 using integrated pharmacophore modeling.
• To screen the DrugBank repository for potential VPS34 inhibitors.
• To evaluate drug-like properties and binding affinity of identified compounds.

Main Methods:

• Development of energy-based and receptor cavity-based pharmacophore models.
• Screening of the DrugBank repository (9591 molecules) against pharmacophore hypotheses.
• In silico evaluation including docking score, binding free energy, and ADMET properties.
• Validation using 50 ns molecular dynamics simulations.

Main Results:

• Identification of five (DHRRR) and seven (AADDHRR) pharmacophore hypotheses.
• DB03916 emerged as a hit molecule with superior docking score and binding affinity compared to a reference compound.
• DB03916 demonstrated favorable drug-like properties and no toxicity concerns.
• Molecular dynamics simulations validated the stability and binding of DB03916.

Conclusions:

• DB03916 is a promising antagonist of VPS34.
• This molecule holds potential for development as a novel cancer therapeutic agent.
• The study highlights the utility of integrated pharmacophore strategies for drug discovery.