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<p>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 IC<sub>50</sub> value of 12.84 ± 2.51&#xa0;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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年11月25日

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  • Abdus Samad,
  • Mussa Yussuf Khamis,
  • Peng Jin,
  • Muhammad Naeem Toor,
  • Yinglan Yu,
  • Lei Luo,
  • Hao Shao

摘要

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.