Header

UZH-Logo

Maintenance Infos

Exploring the Binding Pathway of Novel Nonpeptidomimetic Plasmepsin V Inhibitors


Bobrovs, Raitis; Drunka, Laura; Kanepe, Iveta; Jirgensons, Aigars; Caflisch, Amedeo; Salvalaglio, Matteo; Jaudzems, Kristaps (2023). Exploring the Binding Pathway of Novel Nonpeptidomimetic Plasmepsin V Inhibitors. Journal of Chemical Information and Modeling, 63(21):6890-6899.

Abstract

Predicting the interaction modes and binding affinities of virtual compound libraries is of great interest in drug development. It reduces the cost and time of lead compound identification and selection. Here we apply path-based metadynamics simulations to characterize the binding of potential inhibitors to the Plasmodium falciparum aspartic protease plasmepsin V (plm V), a validated antimalarial drug target that has a highly mobile binding site. The potential plm V binders were identified in a high-throughput virtual screening (HTVS) campaign and were experimentally verified in a fluorescence resonance energy transfer (FRET) assay. Our simulations allowed us to estimate compound binding energies and revealed relevant states along binding/unbinding pathways in atomistic resolution. We believe that the method described allows the prioritization of compounds for synthesis and enables rational structure-based drug design for targets that undergo considerable conformational changes upon inhibitor binding.

Abstract

Predicting the interaction modes and binding affinities of virtual compound libraries is of great interest in drug development. It reduces the cost and time of lead compound identification and selection. Here we apply path-based metadynamics simulations to characterize the binding of potential inhibitors to the Plasmodium falciparum aspartic protease plasmepsin V (plm V), a validated antimalarial drug target that has a highly mobile binding site. The potential plm V binders were identified in a high-throughput virtual screening (HTVS) campaign and were experimentally verified in a fluorescence resonance energy transfer (FRET) assay. Our simulations allowed us to estimate compound binding energies and revealed relevant states along binding/unbinding pathways in atomistic resolution. We believe that the method described allows the prioritization of compounds for synthesis and enables rational structure-based drug design for targets that undergo considerable conformational changes upon inhibitor binding.

Statistics

Citations

Altmetrics

Downloads

2 downloads since deposited on 28 Nov 2023
2 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Scopus Subject Areas:Physical Sciences > General Chemistry
Physical Sciences > General Chemical Engineering
Physical Sciences > Computer Science Applications
Social Sciences & Humanities > Library and Information Sciences
Language:English
Date:6 October 2023
Deposited On:28 Nov 2023 10:01
Last Modified:29 Jun 2024 01:40
Publisher:American Chemical Society (ACS)
ISSN:1549-9596
OA Status:Closed
Publisher DOI:https://doi.org/10.1021/acs.jcim.3c00826
PubMed ID:37801405