7O9W

Encequidar-bound human P-glycoprotein in complex with UIC2-Fab

Summary for 7O9W

• Entry DOI: 10.2210/pdb7o9w/pdb
• EMDB information: 12765
• Descriptor: Multidrug resistance protein 1, UIC2 Fab-fragment light chain, UIC2 Fab-fragment heavy chain, ... (4 entities in total)
• Functional Keywords: abcb1, mdr1, p-glycoprotein, nanodisc, encequidar, transport protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 191712.59

Authors

Nosol, K.,Locher, K.P. (deposition date: 2021-04-17, release date: 2022-01-12, Last modification date: 2024-11-13)

Primary citation

Urgaonkar, S.,Nosol, K.,Said, A.M.,Nasief, N.N.,Bu, Y.,Locher, K.P.,Lau, J.Y.N.,Smolinski, M.P.
Discovery and Characterization of Potent Dual P-Glycoprotein and CYP3A4 Inhibitors: Design, Synthesis, Cryo-EM Analysis, and Biological Evaluations.
J.Med.Chem., 65:191-216, 2022

PubMed Abstract: Targeted concurrent inhibition of intestinal drug efflux transporter P-glycoprotein (P-gp) and drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is a promising approach to improve oral bioavailability of their common substrates such as docetaxel, while avoiding side effects arising from their pan inhibitions. Herein, we report the discovery and characterization of potent small molecule inhibitors of P-gp and CYP3A4 with encequidar (minimally absorbed P-gp inhibitor) as a starting point for optimization. To aid in the design of these dual inhibitors, we solved the high-resolution cryo-EM structure of encequidar bound to human P-gp. The structure guided us to prudently decorate the encequidar scaffold with CYP3A4 pharmacophores, leading to the identification of several analogues with dual potency against P-gp and CYP3A4. , dual P-gp and CYP3A4 inhibitor improved the oral absorption of docetaxel by 3-fold as compared to vehicle, while itself remained poorly absorbed.

PubMed: 34928144
DOI: 10.1021/acs.jmedchem.1c01272

Experimental method

ELECTRON MICROSCOPY (3.5 Å)