Identification & Evaluation of DNA Ligase Inhibitors: Predicting the Binding of Small Molecules to the DNA Binding Domain by Molecular Modeling
Year: 2017
Type: article
Abstract: The phosphodiester backbone of DNA is maintained by DNA ligases. In human cells, there are three genes that encode DNA ligase polypeptides with distinct but overlapping functions. A series of small molecule inhibitors of human DNA ligases were previously identified using a rational structure-based approach. Three of these inhibitors, L82, a DNA ligase I selective inhibitor, and L67, an inhibitor of DNA ligases I and III, and L189, an inhibitor of all three human DNA ligases, have related structures. Here I present and characterize L82-G17 a next-generation ligase I specific inhibitor. L82-G17 is a potent ligase I uncompetitive inhibitor that is shown to act both biochemically and in cell culture models. Furthermore, the binding site for L82 and L82-G17 has been identified via molecular modeling, and verified through mutagenesis.
Author: Timothy Howes
Language: English
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2883151350