A structure-based approach to discover a potential isomerase Pin1 inhibitor for cancer therapy using computational...

Area of Science:

• Biochemistry
• Oncology
• Drug Discovery

Background:

• Peptidyl-prolyl cis/trans isomerase Pin1 is crucial in preventing malignant tumors.
• Pin1 is a significant therapeutic target for various cancers.
• Developing novel Pin1 inhibitors is essential for cancer treatment.

Purpose of the Study:

• To identify FDA-approved drugs as potential Pin1 inhibitors.
• To evaluate the binding affinity and inhibitory activity of candidate drugs against Pin1.
• To explore the potential of drug repurposing for Pin1-targeted cancer therapies.

Main Methods:

• Virtual screening and empirical screening were used to predict Pin1 inhibitors from FDA-approved drug databases.
• Fluorescence titration and PPIase activity assays were employed to test binding affinity and inhibitory activity.
• Cell viability assays and apoptosis studies were conducted to assess the effects of bexarotene.

Main Results:

• Four FDA-approved drugs demonstrated significant binding affinities and inhibitory effects against Pin1.
• Bexarotene exhibited dose- and time-dependent reduction in cell viability and induced apoptosis.
• Key residues (K63, R68, R69) were identified as important for bexarotene-Pin1 binding.

Conclusions:

• Repurposing FDA-approved drugs is a viable strategy for discovering Pin1 inhibitors.
• Bexarotene shows potential as an anti-cancer agent targeting Pin1.
• This study offers promising insights for developing new treatments for malignant tumors by repurposing existing drugs.