Structure-based discovery of novel P-glycoprotein inhibitors targeting the nucleotide binding domains.

ABSTRACT: P-glycoprotein (P-gp), a membrane transport protein overexpressed in certain drug-resistant cancer cells, has been the target of numerous drug discovery projects aimed at overcoming drug resistance in cancer. Most characterized P-gp inhibitors bind at the large hydrophobic drug binding domain (DBD), but none have yet attained regulatory approval. In this study, we explored the potential of designing inhibitors that target the nucleotide binding domains (NBDs), by computationally screening a large library of 2.6 billion synthesizable molecules, using a combination of machine learning-guided molecular docking and molecular dynamics (MD). 14 of the computationally best-scoring molecules were subsequently tested for their ability to inhibit P-gp mediated calcein-AM efflux. In total, five diver

SUBMITTER: Moesgaard L 

PROVIDER: S-EPMC10692163 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature