Significance of interactions of BACE1-Arg235 with its ligands and design of BACE1 inhibitors with P2 pyridine scaffold.
Recently, we reported potent substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. Because these inhibitors contained some natural amino acids, we would need to improve their enzymatic stability in vivo and permeability across the blood-brain barrier, so that they become practically useful. Subsequently, non-peptidic and small-sized BACE1 inhibitors possessing a heterocyclic scaffold, 2,6-pyridenedicarboxylic, chelidamic or chelidonic moiety, at the P(2) position were reported. These inhibitors were designed based on the conformer of docked inhibitor in BACE1. In this study, we discuss the role and significance of interactions between Arg235 of BACE1 and its inhibitor in BACE1 inhibitory mechanism. Moreover, we designed more potent small-sized BACE1 inhibitors with a 2,6-pyridinedicarboxylic scaffold at the P(2) position, that were optimized for the interactions with Arg235 of BACE1.
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Yoshio
Y
Hamada
Hiroko
H
Ohta
Naoko
N
Miyamoto
Diganta
D
Sarma
Takashi
T
Hamada
Tomoya
T
Nakanishi
Moe
M
Yamasaki
Abdellah
A
Yamani
Shoichi
S
Ishiura
Yoshiaki
Y
Kiso
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001120:Arginine / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001812:Blood-Brain Barrier / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008956:Models, Chemical; D008968:Molecular Conformation; D010539:Permeability; D011485:Protein Binding; D011725:Pyridines / Q000037:antagonists & inhibitors* / Q000737:chemistry
D008024:Ligands; D011725:Pyridines; D001120:Arginine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C023666:pyridine