Abstract
Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.
MeSH terms
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1-Alkyl-2-acetylglycerophosphocholine Esterase / antagonists & inhibitors*
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1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism
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Binding Sites / drug effects
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Drug Discovery*
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Models, Molecular
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Molecular Structure
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Structure-Activity Relationship
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Thiazoles / chemical synthesis
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Thiazoles / chemistry
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Thiazoles / pharmacology*
Substances
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Enzyme Inhibitors
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Pyrazoles
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Thiazoles
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1-Alkyl-2-acetylglycerophosphocholine Esterase
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PLA2G7 protein, human