7QYH

Structure of plasmepsin II in complex with 2-aminoquinazolin-4(3H)-one based open-flap inhibitor

This is a non-PDB format compatible entry.

Summary for 7QYH

• Entry DOI: 10.2210/pdb7qyh/pdb
• Descriptor: Plasmepsin II, 2-azanyl-3-[[(2~{R})-oxolan-2-yl]methyl]-7-(5-phenylpentyl)quinazolin-4-one (2 entities in total)
• Functional Keywords: eukaryotic aspartic protease, malaria, plasmepsin, hydrolase
• Biological source: Plasmodium falciparum 3D7
• Total number of polymer chains: 4
• Total formula weight: 148029.97

Authors

Bobrovs, R.,Jaudzems, K. (deposition date: 2022-01-28, release date: 2022-06-29, Last modification date: 2024-10-16)

Primary citation

Bobrovs, R.,Basens, E.E.,Drunka, L.,Kanepe, I.,Matisone, S.,Velins, K.K.,Andrianov, V.,Leitis, G.,Zelencova-Gopejenko, D.,Rasina, D.,Jirgensons, A.,Jaudzems, K.
Exploring Aspartic Protease Inhibitor Binding to Design Selective Antimalarials.
J.Chem.Inf.Model., 62:3263-3273, 2022

PubMed Abstract: Selectivity is a major issue in the development of drugs targeting pathogen aspartic proteases. Here, we explore the selectivity-determining factors by studying specifically designed malaria aspartic protease (plasmepsin) open-flap inhibitors. Metadynamics simulations are used to uncover the complex binding/unbinding pathways of these inhibitors and describe the critical transition states in atomistic resolution. The simulation results are compared with experimentally determined enzymatic activities. Our findings demonstrate that plasmepsin inhibitor selectivity can be achieved by targeting the flap loop with hydrophobic substituents that enable ligand binding under the flap loop, as such a behavior is not observed for several other aspartic proteases. The ability to estimate the selectivity of compounds before they are synthesized is of considerable importance in drug design; therefore, we expect that our approach will be useful in selective inhibitor designs against not only aspartic proteases but also other enzyme classes.

PubMed: 35712895
DOI: 10.1021/acs.jcim.2c00422

Experimental method

X-RAY DIFFRACTION (3.33 Å)