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High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
Published on: May 5, 2014
Identification of novel VPS4 inhibitors using multi-tiered structure based virtual screening
Abdus Samad1, Mussa Yussuf Khamis1, Peng Jin1
1College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.
Abstract:
Vacuolar protein sorting 4 (VPS4) is an AAA-ATPase that mediates ESCRT-III disassembly critical for membrane remodeling events like autophagosome closure and endolysosomal repair. Aberrant expression of VPS4 is associated with cancer progression and poor prognosis, making VPS4 a potential anticancer target. To date, very few VPS4 inhibitors have been reported, therefore the identification and development of VPS4 inhibitors is urgently needed. In this study, we employed a multi-tiered structure based virtual screening strategy, molecular dynamic simulation accompanied by pharmacokinetic analysis and in vitro screening to identify novel inhibitors of VPS4. The identified inhibitor comp-23 effectively inhibited the enzymatic activity of VPS4B with an IC50 value of 12.84 ± 2.51 µM. Protein ligand interaction profile and molecular dynamic simulation revealed the ATP binding residues such as Ala137, Gly177, Glu179, Asn279, and His313 were the main contributors to the binding of this compound. Comp-23 serves as a hit compound for further optimization to explore VPS4-related functions.
Insights
Researchers identified a novel inhibitor, comp-23, targeting Vacuolar protein sorting 4 (VPS4), an enzyme linked to cancer. This discovery offers a promising avenue for developing new anticancer therapies by inhibiting VPS4 activity.
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.
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