Identification of novel VPS4 inhibitors using multi-tiered structure based virtual screening

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Vacuolar protein sorting 4 (VPS4) is an AAA-ATPase crucial for membrane remodeling.
• VPS4 dysfunction is implicated in cancer progression and poor prognosis, highlighting its potential as an anticancer target.
• Limited availability of VPS4 inhibitors necessitates the search for novel therapeutic agents.

Purpose of the Study:

• To identify novel inhibitors of VPS4 using a structure-based virtual screening approach.
• To evaluate the inhibitory potential of identified compounds against VPS4 enzymatic activity.
• To elucidate the binding mechanism of the identified inhibitor with VPS4.

Main Methods:

• Multi-tiered structure-based virtual screening.
• Molecular dynamic simulations.
• Pharmacokinetic analysis.
• In vitro enzymatic assays.
• Protein-ligand interaction profiling.

Main Results:

• Identification of comp-23 as a novel VPS4 inhibitor.
• Comp-23 demonstrated effective inhibition of VPS4B enzymatic activity with an IC50 of 12.84 ± 2.51 µM.
• Molecular dynamics and interaction analysis revealed key binding residues in the ATP-binding site (Ala137, Gly177, Glu179, Asn279, His313).

Conclusions:

• Comp-23 is a promising hit compound for further optimization.
• The identified inhibitor provides a foundation for developing targeted VPS4-based cancer therapies.
• Further studies are warranted to explore VPS4-related functions and therapeutic applications of comp-23.