Novel Substrate-Based Inhibitors of Human Glutamate Carboxypeptidase II with Enhanced Lipophilicity

详细信息    查看全文

• 作者：Anna Plechanovov谩 ; Youngjoo Byun ; Glenda Alquicer ; L'ubica 艩kult茅tyov谩 ; Petra Ml膷ochov谩 ; Adriana N臎mcov谩 ; Hyung-Joon Kim ; Michal Navr谩til ; Ronnie Mease ; Jacek Lubkowski ; Martin Pomper ; Jan Konvalinka ; Lubom铆r Rul铆拧ek ; Cyril Ba艡inka
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 10, 2011
• 年：2011
• 卷：54
• 期：21
• 页码：7535-7546
• 全文大小：1082K
• 年卷期：v.54,no.21(November 10, 2011)
• ISSN：1520-4804

文摘

Virtually all low molecular weight inhibitors of human glutamate carboxypeptidase II (GCPII) are highly polar compounds that have limited use in settings where more lipophilic molecules are desired. Here we report the identification and characterization of GCPII inhibitors with enhanced liphophilicity that are derived from a series of newly identified dipeptidic GCPII substrates featuring nonpolar aliphatic side chains at the C-terminus. To analyze the interactions governing the substrate recognition by GCPII, we determined crystal structures of the inactive GCPII(E424A) mutant in complex with selected dipeptides and complemented the structural data with quantum mechanics/molecular mechanics calculations. Results reveal the importance of nonpolar interactions governing GCPII affinity toward novel substrates as well as formerly unnoticed plasticity of the S1鈥?specificity pocket. On the basis of those data, we designed, synthesized, and evaluated a series of novel GCPII inhibitors with enhanced lipophilicity, with the best candidates having low nanomolar inhibition constants and clogD > 鈭?.3. Our findings offer new insights into the design of more lipophilic inhibitors targeting GCPII.