Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening

Autor:	Kirsten V. Smith, Joseph E. Pero, Ralph A. Rivero, Donald O. Somers, Vipulkumar Kantibhai Patel, Agnes C. L. Martin, Rachel McMenamin, Sridhar Aravapalli, Finn P. Holding, Eric S. Manas, Lionel Trottet, Alison Jo-Anne Woolford, Neipp Christopher E, Lydia Y. W. Lee, Ranganadh Velagaleti, Sharna J. Rich, Ren Xie, Peng Li, Glyn Williams, Andrew M. Dodson, Brent W. Mccleland, Lee William Page, Joseph P. Marino, Pascal Grondin, Florent Potvain, Joseph E. Coyle, Christopher William Murray, Philip J. Day, Valerio Berdini
Rok vydání:	2016
Předmět:	Models Molecular 0301 basic medicine Stereochemistry Drug Evaluation Preclinical Crystallography X-Ray Structure-Activity Relationship 03 medical and health sciences Phospholipase A2 Drug Discovery Hydrolase Humans Structure–activity relationship Enzyme Inhibitors Binding site Binding Sites Dose-Response Relationship Drug Molecular Structure biology Chemistry Drug discovery Lipoprotein-associated phospholipase A2 Active site 1-Alkyl-2-acetylglycerophosphocholine Esterase Thiazoles 030104 developmental biology Biochemistry biology.protein Pyrazoles Molecular Medicine lipids (amino acids peptides and proteins)
Zdroj:	Journal of Medicinal Chemistry. 59:5356-5367
ISSN:	1520-4804 0022-2623
DOI:	10.1021/acs.jmedchem.6b00212
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2d7919286100bbcfc9e76bca6023c7c4 https://doi.org/10.1021/acs.jmedchem.6b00212 Zobrazit plný text záznamu