4trz › Citations

Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors.

Hattori Y, Kobayashi K, Deguchi A, Nohara Y, Akiyama T, Teruya K, Sanjoh A, Nakagawa A, Yamashita E, Akaji K
Bioorg Med Chem 23 5626-40 (2015)
Cited: 5 times
EuropePMC logo PMID: 26264846

Abstract

A superior substrate sequence for BACE1 containing transition-state mimics at the scissile site was evaluated as a protease inhibitor. Hydroxymethylcarbonyl (HMC) and hydroxyethylamine (HEA) isosteres were selected as the transition state mimics, and incorporated into the scissile site of the superior sequence covering the P4 to P1' sites (Glu-Ile-Thi-Thi(*)Nva; (*)denotes the cleavage site). Isosteres having different absolute configurations of the hydroxyl group were synthesized separately, and the effect of the configuration was evaluated. Configuration of the hydroxyl group of each isostere showed a marked effect on the inhibitory activity; anti-configuration to the scissile site substituent had potent inhibitory activity in an HMC-type inhibitor, whereas anti-configuration of HEA-type inhibitors showed no inhibitory activity. Structural evaluations based on X-ray crystallographic analyses of recombinant BACE1 in complex with each inhibitor provided insights into the protein-ligand interactions, especially at the prime sites.

Articles - 4trz mentioned but not cited (1)

  1. Partial Characterization of Two Cathepsin D Family Aspartic Peptidases of Clonorchis sinensis. Kang JM, Yoo WG, Lê HG, Thái TL, Hong SJ, Sohn WM, Na BK. Korean J Parasitol 57 671-680 (2019)


Reviews citing this publication (1)

  1. Development and Structural Modification of BACE1 Inhibitors. Gu T, Wu WY, Dong ZX, Yu SP, Sun Y, Zhong Y, Lu YT, Li NG. Molecules 22 E4 (2016)

Articles citing this publication (3)

  1. Performance evaluation of molecular docking and free energy calculations protocols using the D3R Grand Challenge 4 dataset. Elisée E, Gapsys V, Mele N, Chaput L, Selwa E, de Groot BL, Iorga BI. J Comput Aided Mol Des 33 1031-1043 (2019)
  2. Development of an Efficient Enzyme Production and Structure-Based Discovery Platform for BACE1 Inhibitors. Yen YC, Kammeyer AM, Jensen KC, Tirlangi J, Ghosh AK, Mesecar AD. Biochemistry 58 4424-4435 (2019)
  3. Cyanomethyl anion transfer reagents for diastereoselective Corey-Chaykovsky cyclopropanation reactions. Hommelsheim R, Hock KJ, Schumacher C, Hussein MA, Nguyen TV, Koenigs RM. Chem Commun (Camb) 54 11439-11442 (2018)


Quick links