Structure-based design of novel human Pin1 inhibitors (I)

Pin1 is a member of the cis–trans peptidyl-prolyl isomerase family with potential anti-cancer therapeutic value. Here we report structure-based de novo design and optimization of novel Pin1 inhibitors. Without a viable lead from internal screenings, we designed a series of novel Pin1 inhibitors by interrogating and exploring a protein crystal structure of Pin1. The ligand efficiency of the initial concept molecule was optimized with integrated SBDD and parallel chemistry approaches, resulting in a more attractive lead series.

Graphical abstractA series of novel non-peptide small molecular PIN1 inhibitors was discovered utilizing SBDD and combinatorial approach. The simplified pharmacophore opens the door for other drug-like Pin-1 inhibitor design.Figure optionsDownload full-size imageDownload as PowerPoint slide