Exploring Aspartic Protease Inhibitor Binding to Design Selective Antimalarials
Journal of Chemical Information and Modeling 2022
Raitis Bobrovs, Emīls Edgars Basens, Laura Drunka, Iveta Kanepe, Sofija matisone, Karlis Kristofers Velins, Victor Andrianov, Gundars Leitis, Diāna Zeļencova-Gopejenko, Dace Rasiņa, Aigars Jirgensons, Kristaps Jaudzems

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.


Atslēgas vārdi
HIV-1 Protease, Plasmepsin-Ii, Malaria Parasite, Plasmodium-Falciparum, Molecular-Dynamics, Flap Dynamics, Funnel-Metadynamics, NMR, IX, Resistance
DOI
10.1021/acs.jcim.2c00422
Hipersaite
https://pubs.acs.org/doi/10.1021/acs.jcim.2c00422

Bobrovs, R., Basens, E., Drunka, L., Kanepe, I., Matisone, S., Velins, K., Andrianov, V., Leitis, G., Zeļencova-Gopejenko, D., Rasiņa, D., Jirgensons, A., Jaudzems, K. Exploring Aspartic Protease Inhibitor Binding to Design Selective Antimalarials. Journal of Chemical Information and Modeling, 2022, Vol. 62, No. 13, 3263.-3273.lpp. ISSN 1549-9596. Pieejams: doi:10.1021/acs.jcim.2c00422

Publikācijas valoda
English (en)
RTU Zinātniskā bibliotēka.
E-pasts: uzzinas@rtu.lv; Tālr: +371 28399196