Repurposing human PDE4 inhibitors for neglected tropical diseases. Evaluation of analogs of the human PDE4 inhibitor GSK-256066 as inhibitors of PDEB1 of Trypanosoma brucei
| Autor: | Stefan O. Ochiana, Nicholas D. Bland, Robert K. Campbell, Luca Settimo, Michael P. Pollastri |
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| Rok vydání: | 2014 |
| Předmět: |
Trypanosoma brucei brucei
Protozoan Proteins Trypanosoma brucei Pharmacology Biochemistry Article Structure-Activity Relationship Drug Discovery medicine Potency Humans African trypanosomiasis Sulfones Repurposing chemistry.chemical_classification Binding Sites biology Cell growth Organic Chemistry Drug Repositioning Phosphodiesterase Neglected Diseases medicine.disease biology.organism_classification Cyclic Nucleotide Phosphodiesterases Type 4 Protein Structure Tertiary Molecular Docking Simulation Enzyme Trypanosomiasis African Drug development chemistry 3' 5'-Cyclic-AMP Phosphodiesterases Aminoquinolines Quinolines Molecular Medicine Phosphodiesterase 4 Inhibitors |
| Zdroj: | Chemical biologydrug design. 85(5) |
| ISSN: | 1747-0285 |
| Popis: | Cyclic nucleotide phosphodiesterases (PDEs) have been identified as important enzyme targets for drug development in both humans and Trypanosoma brucei, the causative agent of human African trypanosomiasis. With this in mind, we recently reported the profiling of a range of human phosphodiesterase inhibitors, showing that human PDE4 inhibitors tend to display the best potency against the trypanosomal phosphodiesterase TbrPDEB1. Among these was GSK-256066, a potent inhibitor of human PDE4 and a weak inhibitor of TbrPDEB1. In this report, we describe the results of a structure-activity relationship study of this chemotype, leading to the discovery of analogs with improved potency against TbrPDEB1 and micromolar inhibition of T. brucei cellular growth. We rationalize the potency trends via molecular docking of the new inhibitors into a recently reported apo structure of TbrPDEB1. The studies in this article will inform future efforts in repurposing human PDE inhibitors as antitrypanosomal agents. |
| Databáze: | OpenAIRE |
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