| Literature DB >> 26195137 |
Melissa Egbertson1, Georgia B McGaughey2, Steven M Pitzenberger3, Shaun R Stauffer4, Craig A Coburn4, Shawn J Stachel4, Wenjin Yang5, James C Barrow4, Lou Anne Neilson4, Melody McWherter4, Debra Perlow4, Bruce Fahr5, Sanjeev Munshi6, Timothy J Allison7, Katharine Holloway2, Harold G Selnick8, ZhiQiang Yang4, John Swestock9, Adam J Simon10, Sethu Sankaranarayanan10, Dennis Colussi10, Katherine Tugusheva10, Ming-Tain Lai10, Beth Pietrak10, Shari Haugabook10, Lixia Jin11, I-W Chen11, Marie Holahan12, Maria Stranieri-Michener12, Jacquelynn J Cook12, Joseph Vacca4, Samuel L Graham4.
Abstract
The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 μM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.Entities:
Keywords: Amyloid; Beta secretase; Magic methyl effect; Spiropiperidine
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Year: 2015 PMID： 26195137 DOI： 10.1016/j.bmcl.2015.06.082
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823