Scaffold Hopping and Optimization of Thiazole Hybrids as Selective PIN1 Inhibitors: A Computational Study

Area of Science:

• Medicinal Chemistry
• Computational Drug Design
• Enzymology

Background:

• Protein Interacting with NIMA1 (PIN1) is a peptidyl-prolyl cis-trans isomerase (PPIase) enzyme.
• PIN1 catalyzes isomerization of pSer/Thr-Pro motifs, presenting a therapeutic target for multiple disorders.

Purpose of the Study:

• To discover novel scaffolds for effective PIN1 inhibitors.
• To identify potential therapeutic leads for diseases like cancer, diabetes, and Alzheimer's.

Main Methods:

• Designed 140 thiazole compounds using shape similarity.
• Performed molecular docking and calculated binding free energies.
• Evaluated ADMET properties and conducted molecular dynamics simulations.

Main Results:

• Identified 16 potential PIN1 inhibitors based on computational analysis.
• Four compounds (S8Ba, S8Bb, S8Bd, S8Be) showed favorable ADMET profiles and strong interactions with PIN1.
• Molecular dynamics simulations confirmed S8Ba and S8Bd as highly promising candidates.

Conclusions:

• Computational findings validated the identified compounds as potential PIN1 inhibitors.
• This study provides a foundation for developing new therapeutics targeting PIN1.
• The identified compounds could lead to treatments for diabetes, cancer, and Alzheimer's disease.