TY - JOUR
T1 - Asp32 and Asp228 determine the selective inhibition of BACE1 as shown by docking and molecular dynamics simulations
AU - Hernández-Rodríguez, Maricarmen
AU - Correa-Basurto, José
AU - Gutiérrez, Antonia
AU - Vitorica, Javier
AU - Rosales-Hernández, Martha C.
N1 - Publisher Copyright:
© 2016 Elsevier Masson SAS
PY - 2016
Y1 - 2016
N2 - Inhibition of β-site amyloid–β-protein precursor cleaving enzyme 1 (BACE1) represents a promising approach for the treatment of Alzheimer's disease (AD). However, the development of a selective BACE1 inhibitor is difficult due to its highly flexible catalytic site and homology to other aspartic proteases, including BACE2 and Cathepsin D (CTSD). Aiming to better understand the structural factors responsible for selective BACE1 inhibition, we performed alignment studies, molecular dynamics (MD) simulations and docking studies to explore the recognition of four selective BACE1 inhibitors by aspartyl proteases. The results show that selective BACE1 inhibition may be due to the formation of strong electrostatic interactions with Asp32 and Asp228 and a large number of hydrogen bonds, π-π and Van der Waals interactions with the amino acid residues located inside the catalytic cavity, which has different volume and shape compared to BACE2 and CTSD. Hindrance effects avoid the accommodation of ligands in the small catalytic site of BACE2, resulting in a lower affinity and the high cavity of CTSD results in the formation of a small number of interactions with the ligands, although they show a similar binding mode with BACE1. These results might help to rationalize the design of selective BACE1 inhibitors.
AB - Inhibition of β-site amyloid–β-protein precursor cleaving enzyme 1 (BACE1) represents a promising approach for the treatment of Alzheimer's disease (AD). However, the development of a selective BACE1 inhibitor is difficult due to its highly flexible catalytic site and homology to other aspartic proteases, including BACE2 and Cathepsin D (CTSD). Aiming to better understand the structural factors responsible for selective BACE1 inhibition, we performed alignment studies, molecular dynamics (MD) simulations and docking studies to explore the recognition of four selective BACE1 inhibitors by aspartyl proteases. The results show that selective BACE1 inhibition may be due to the formation of strong electrostatic interactions with Asp32 and Asp228 and a large number of hydrogen bonds, π-π and Van der Waals interactions with the amino acid residues located inside the catalytic cavity, which has different volume and shape compared to BACE2 and CTSD. Hindrance effects avoid the accommodation of ligands in the small catalytic site of BACE2, resulting in a lower affinity and the high cavity of CTSD results in the formation of a small number of interactions with the ligands, although they show a similar binding mode with BACE1. These results might help to rationalize the design of selective BACE1 inhibitors.
KW - Alzheimer
KW - Beta secretases
KW - Docking molecular dynamics simulations
KW - Molecular modeling
UR - http://www.scopus.com/inward/record.url?scp=84995688375&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2016.08.028
DO - 10.1016/j.ejmech.2016.08.028
M3 - Artículo
C2 - 27639619
SN - 0223-5234
VL - 124
SP - 1142
EP - 1154
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -