Computer-Aided Lead Optimization: Improved Small-Molecule Inhibitor of the Zinc Endopeptidase of Botulinum Neurotoxin Serotype A
Open Access
- 22 August 2007
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 2 (8), e761
- https://doi.org/10.1371/journal.pone.0000761
Abstract
Optimization of a serotype-selective, small-molecule inhibitor of botulinum neurotoxin serotype A (BoNTA) endopeptidase is a formidable challenge because the enzyme-substrate interface is unusually large and the endopeptidase itself is a large, zinc-binding protein with a complex fold that is difficult to simulate computationally. We conducted multiple molecular dynamics simulations of the endopeptidase in complex with a previously described inhibitor (Kiapp of 7±2.4 µM) using the cationic dummy atom approach. Based on our computational results, we hypothesized that introducing a hydroxyl group to the inhibitor could improve its potency. Synthesis and testing of the hydroxyl-containing analog as a BoNTA endopeptidase inhibitor showed a twofold improvement in inhibitory potency (Kiapp of 3.8±0.8 µM) with a relatively small increase in molecular weight (16 Da). The results offer an improved template for further optimization of BoNTA endopeptidase inhibitors and demonstrate the effectiveness of the cationic dummy atom approach in the design and optimization of zinc protease inhibitors.Keywords
This publication has 49 references indexed in Scilit:
- An in vitro and in vivo disconnect uncovered through high-throughput identification of botulinum neurotoxin A antagonistsProceedings of the National Academy of Sciences, 2007
- Inhibition of Metalloprotease Botulinum Serotype A from a Pseudo-peptide Binding Mode to a Small Molecule That Is Active in Primary NeuronsJournal of Biological Chemistry, 2007
- Synthesis, Characterization and Development of a High-Throughput Methodology for the Discovery of Botulinum Neurotoxin A InhibitorsJournal of Combinatorial Chemistry, 2006
- Identification of a Potent Botulinum Neurotoxin A Protease Inhibitor Using in Situ Lead Identification ChemistryOrganic Letters, 2006
- Small-molecule inhibitors of protein–protein interactions: progressing towards the dreamNature Reviews Drug Discovery, 2004
- Zinc′s Exclusive Tetrahedral Coordination Governed by Its Electronic StructureJournal of Molecular Modeling, 1999
- AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of moleculesComputer Physics Communications, 1995
- Molecular dynamics with coupling to an external bathThe Journal of Chemical Physics, 1984
- Inhibition of angiotensin converting enzyme: mechanism and substrate dependenceBiochemistry, 1984
- Comparison of simple potential functions for simulating liquid waterThe Journal of Chemical Physics, 1983