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

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• 作者：Alison J.-A. Woolford ; Joseph E. Pero ; Sridhar Aravapalli ; Valerio Berdini ; Joseph E. Coyle ; Philip J. Day ; Andrew M. Dodson ; Pascal Grondin ; Finn P. Holding ; Lydia Y. W. Lee ; Peng Li ; Eric S. Manas ; Joseph Marino Jr. ; Agnes C. L. Martin ; Brent W. McCleland ; Rachel L. McMenamin ; Christopher W. Murray ; Christopher E. Neipp ; Lee W. Page ; Vipulkumar K. Patel ; Florent Potvain ; Sharna Rich ; Ralph A. Rivero ; Kirsten Smith ; Donald O. Somers ; Lionel Trottet ; Ranganadh Velagaleti ; Glyn Williams ; Ren Xie
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：June 9, 2016
• 年：2016
• 卷：59
• 期：11
• 页码：5356-5367
• 全文大小：763K
• 年卷期：0
• ISSN：1520-4804

文摘

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.