GOLD in Action: Foiling a Protein–Protein Interaction to Help Fight Cancer – Drug Repurposing using GOLD
April 26, 2023
Reporting in the Journal of Medicinal Chemistry, a team of computational chemists, structural biologists, and biochemists used GOLD and CHEMPLP-based ranking to identify an approved drug as an inhibitor of a key protein–protein interaction (PPI) in the fight against cancer.
The nuclear export receptor exportin-1 (XPO1) protein is overexpressed in many cancer types and an attractive cancer drug target that has been the center of a several development programs. For example, the recently approved covalent XPO1 inhibitor Selinexor was the culmination of such a program. However, non-covalent inhibitors may offer better safety and efficacy profiles along with increased resilience to resistance.
Prepared structures of the approved drugs were docked into the XPO1 active site. Docking studies were performed using GOLD. Docked poses were scored using CCDC’s CHEMPLP, and the researchers ranked the poses by the CHEMPLP scores.
Finding Their Groove
Based on the output of GOLD, zafirlukast was identified as a non-covalent binder of XPO1 first using an ‘NES-pulldown’ assay and then, in the presence of RanGTP, through further in vitro studies. Zafirlukast displayed activity against a broad range of cancer types in vitro, and synergy was observed when combined with doxorubicin. The researchers also observed resilience to the C528S mutation, an obstacle to other ligands. Molecular docking with GOLD further suggested that m-tolyl and p-tolyl zafirlukast derivatives were compatible with the nuclear export signal (NES) groove. Zafirlukast closely matched the shape of the markedly flexible NES groove, based on the Zafirlukast-XPO1 crystal structure obtained by the researchers (see Figure), and the observed interaction was entirely hydrophobic.
Read the full paper – Searching for Novel Noncovalent Nuclear Export Inhibitors through a Drug Repurposing Approach. J. Med. Chem. 2023, 66, 1574−1582. https://doi.org/10.1021/acs.jmedchem.2c01772.
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