Peptoid Cancer Drugs Targeting PCNA Designed via a Novel in Silico/In Vitro Pipeline

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Fragment-based drug discovery is a popular method used to design molecules that bind to protein targets. In this method, many small compounds are screened for their binding to a target protein. Subsequently, steps are undertaken to combine more than one of the small compounds found to bind weakly into a larger, stronger-binding, drug-like compound. Fragment-based drug discovery presents a significant challenge; information must be known about the binding sites of the fragments so that they can be combined in a way that does not disrupt the binding of the individual fragments. In addition, many important drug target proteins participate in protein-protein interactions. Disrupting such interactions is critical to disrupting the chemical signals that drive cancer and other diseases.

To overcome the challenges of traditional fragment-based drug design, researchers at Purdue University used a combination of computational and experimental technique to discover novel inhibitors of the interaction between proliferating cell nuclear antigen (PCNA) and a peptide that binds to a site on PCNA responsible for multiple protein-protein interactions relevant to its cellular function. Specifically, thousands of tripeptoids (peptide-like molecules with three chemically distinct sites) were screened in silico, facilitating the selection of a small number of tripeptoids for in vitro testing. Several of the selected tripeptoids show a good ability to disrupt the PCNA-peptide interaction. This method of drug discovery successfully identified a small number of hit compounds that disrupt a protein-protein interaction involving PCNA, an important cancer target.

-Potential first-in-class cancer drug
-Fewer compounds synthesized
-Less structural information needed than in traditional fragment-based drug discovery
-Well-suited to targeting protein-protein interactions

Potential Applications:
-Drug discovery
-Cancer therapy
Jun 6, 2018
United States
Sep 1, 2020

Aug 12, 2020
CON-Gov. Funding
United States

Dec 6, 2016

Dec 7, 2015
United States
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