Antoni R Blaazer, Abhimanyu K Singh, Lorena Zara, Pierre Boronat, Lady J Bautista, Steve Irving, Maciej Majewski, Xavier Barril, Maikel Wijtmans, U Helena Danielson, Geert Jan Sterk, Rob Leurs, Jacqueline E van Muijlwijk-Koezen, David G Brown, Iwan de Esch
In search of new opportunities to develop Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) inhibitors that have selectivity over the off-target human PDE4 (hPDE4), different stages of a fragment-growing campaign were studied using a variety of biochemical, structural, thermodynamic, and kinetic binding assays. Remarkable differences in binding kinetics were identified and this kinetic selectivity was explored with computational methods, including molecular dynamics and interaction fingerprint analyses. These studies indicate that a key hydrogen bond between GlnQ.50 and the inhibitors is exposed to a water channel in TbrPDEB1, leading to fast unbinding. This water channel is not present in hPDE4, leading to inhibitors with a longer residence time. The computer-aided drug design protocols were applied to a recently disclosed TbrPDEB1 inhibitor with a different scaffold and our results confirm that shielding this key hydrogen bond through disruption of the water channel represents a viable design strategy to develop more selective inhibitors of TbrPDEB1. Our work shows how computational protocols can be used to understand the contribution of solvent dynamics to inhibitor binding, and our results can be applied in the design of selective inhibitors for homologous PDEs found in related parasites.
{"title":"The Role of Water Networks in Phosphodiesterase Inhibitor Dissociation and Kinetic Selectivity.","authors":"Antoni R Blaazer, Abhimanyu K Singh, Lorena Zara, Pierre Boronat, Lady J Bautista, Steve Irving, Maciej Majewski, Xavier Barril, Maikel Wijtmans, U Helena Danielson, Geert Jan Sterk, Rob Leurs, Jacqueline E van Muijlwijk-Koezen, David G Brown, Iwan de Esch","doi":"10.1002/cmdc.202400417","DOIUrl":"https://doi.org/10.1002/cmdc.202400417","url":null,"abstract":"<p><p>In search of new opportunities to develop Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) inhibitors that have selectivity over the off-target human PDE4 (hPDE4), different stages of a fragment-growing campaign were studied using a variety of biochemical, structural, thermodynamic, and kinetic binding assays. Remarkable differences in binding kinetics were identified and this kinetic selectivity was explored with computational methods, including molecular dynamics and interaction fingerprint analyses. These studies indicate that a key hydrogen bond between GlnQ.50 and the inhibitors is exposed to a water channel in TbrPDEB1, leading to fast unbinding. This water channel is not present in hPDE4, leading to inhibitors with a longer residence time. The computer-aided drug design protocols were applied to a recently disclosed TbrPDEB1 inhibitor with a different scaffold and our results confirm that shielding this key hydrogen bond through disruption of the water channel represents a viable design strategy to develop more selective inhibitors of TbrPDEB1. Our work shows how computational protocols can be used to understand the contribution of solvent dynamics to inhibitor binding, and our results can be applied in the design of selective inhibitors for homologous PDEs found in related parasites.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Janosch Baumgarten, Philipp Schneider, Marie Thiemann, Moritz Zimmermann, Christina Diederich, Wulf Blankenfeldt, Conrad Kunick
The phenazine pyocyanin is an important virulence factor of the pathogen Pseudomonas aeruginosa, which is on the WHO list of antibiotic resistant "priority pathogens". In this study the isomerase PhzF, a key bacterial enzyme of the pyocyanin biosynthetic pathway, was investigated as a pathoblocker target. The aim of the pathoblocker strategy is to reduce the virulence of the pathogen without killing it, thus preventing the rapid development of resistance. Based on crystal structures of PhzF, derivatives of the inhibitor 3-hydroxyanthranilic acid were designed. Co-crystal structures of the synthesized derivatives with PhzF revealed spacial limitations of the binding pocket of PhzF in the closed conformation. In contrast, ligands aligned to the open conformation of PhzF provided more room for structural modifications. The intrinsic fluorescence of small 3-hydroxyanthranilic acid derivatives enabled direct affinity determinations using FRET assays. The analysis of structure-activity relationships showed that the carboxylic acid moiety is essential for binding to the target enzyme. The results of this study provide fundamental structural insights that will be useful for the design of PhzF-inhibitors.
{"title":"Substrate-Based Ligand Design for Phenazine Biosynthesis Enzyme PhzF.","authors":"Janosch Baumgarten, Philipp Schneider, Marie Thiemann, Moritz Zimmermann, Christina Diederich, Wulf Blankenfeldt, Conrad Kunick","doi":"10.1002/cmdc.202400466","DOIUrl":"https://doi.org/10.1002/cmdc.202400466","url":null,"abstract":"<p><p>The phenazine pyocyanin is an important virulence factor of the pathogen Pseudomonas aeruginosa, which is on the WHO list of antibiotic resistant \"priority pathogens\". In this study the isomerase PhzF, a key bacterial enzyme of the pyocyanin biosynthetic pathway, was investigated as a pathoblocker target. The aim of the pathoblocker strategy is to reduce the virulence of the pathogen without killing it, thus preventing the rapid development of resistance. Based on crystal structures of PhzF, derivatives of the inhibitor 3-hydroxyanthranilic acid were designed. Co-crystal structures of the synthesized derivatives with PhzF revealed spacial limitations of the binding pocket of PhzF in the closed conformation. In contrast, ligands aligned to the open conformation of PhzF provided more room for structural modifications. The intrinsic fluorescence of small 3-hydroxyanthranilic acid derivatives enabled direct affinity determinations using FRET assays. The analysis of structure-activity relationships showed that the carboxylic acid moiety is essential for binding to the target enzyme. The results of this study provide fundamental structural insights that will be useful for the design of PhzF-inhibitors.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dr. Wenjie Liu, Amr A. K. Mousa, Austin M. Hopkins, Yin Fang Wu, Dr. Kelsie L. Thu, Dr. Michael Campbell, Dr. Simon J. Lees, Dr. Rithwik Ramachandran, Dr. Jinqiang Hou
The Front Cover shows a migrastatic candidate (LPA1 antagonist) that effectively suppresses triple-negative breast cancer (TNBC) migration and invasion, crucial processes leading to secondary tumors. Metastasis is responsible for about 90% of cancer mortality, while migrastatics, devoid of cytotoxicity, present a promising avenue to combat metastasis without inducing drug resistance. The findings offer hope for therapeutic interventions in the formidable realm of triple-negative breast cancer—a highly aggressive subtype. More details can be found in article 10.1002/cmdc.202400013 by Jinqiang Hou and co-workers. Cover design by Prof. Jinqiang Hou.