Structure-Based Virtual Screening of New Skp1 Inhibitor Chemotypes Targeting F-Box Binding Interface

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Cancer Therapeutics

Background:

• Skp1 (Skip protein 1) is a validated target for cancer treatment.
• Existing Skp1 inhibitors lack structural diversity and specificity.
• Novel chemical scaffolds are needed for potent and selective Skp1 inhibition.

Purpose of the Study:

• To identify novel chemical scaffolds targeting Skp1.
• To develop potent and specific Skp1 inhibitors for cancer therapy.

Main Methods:

• Structure-based virtual screening (SBVS) of ~280,000 compounds.
• Molecular dynamics (MD) simulations targeting the Skp1 P1 hotspot.
• In vitro biophysical (TSA, FP assays) and biochemical validation.
• Cell viability assays across cancer cell lines.

Main Results:

• 28 potential Skp1 inhibitor hits were identified via SBVS.
• Several compounds demonstrated direct binding to Skp1.
• Compounds #03, #05, #07, #09, #22, #24, and #28 inhibited Skp1:F-box interaction.
• Compounds #04, #12, and #24 exhibited low-to-moderate micromolar EC50 values in cell viability assays.

Conclusions:

• Compounds #04, #12, and #24 represent promising scaffolds for Skp1 inhibitor development.
• These scaffolds can serve as starting points for structure-activity relationship (SAR) studies.
• Future research may lead to a new class of selective Skp1 inhibitors for cancer treatment.