Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: Conformational analysis and binding mode of multisite inhibitors

PloS One
Ornella Di PietroF Javier Luque

Abstract

The critical role of BACE-1 in the formation of neurotoxic ß-amyloid peptides in the brain makes it an attractive target for an efficacious treatment of Alzheimer's disease. However, the development of clinically useful BACE-1 inhibitors has proven to be extremely challenging. In this study we examine the binding mode of a novel potent inhibitor (compound 1, with IC50 80 nM) designed by synergistic combination of two fragments-huprine and rhein-that individually are endowed with very low activity against BACE-1. Examination of crystal structures reveals no appropriate binding site large enough to accommodate 1. Therefore we have examined the conformational flexibility of BACE-1 through extended molecular dynamics simulations, paying attention to the highly flexible region shaped by loops 8-14, 154-169 and 307-318. The analysis of the protein dynamics, together with studies of pocket druggability, has allowed us to detect the transient formation of a secondary binding site, which contains Arg307 as a key residue for the interaction with small molecules, at the edge of the catalytic cleft. The formation of this druggable "floppy" pocket would enable the binding of multisite inhibitors targeting both catalytic and secondary sites....Continue Reading

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Citations

Jun 7, 2018·PloS One·Ammu Prasanna Kumar, Suryani Lukman
Sep 29, 2018·Journal of Molecular Recognition : JMR·Daniel J MermelsteinRoss C Walker
Jun 21, 2017·Future Medicinal Chemistry·Francisco Javier Pérez-ArealesDiego Muñoz-Torrero
Jun 18, 2020·International Journal of Molecular Sciences·Divya BafnaArtem Cherkasov
Oct 29, 2020·Communications Biology·Igor Kozlovskii, Petr Popov
Jul 25, 2020·Journal of Medicinal Chemistry·F Javier Pérez-ArealesDiego Muñoz-Torrero

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Methods Mentioned

BETA
X-ray
PCA
two hybrid

Software Mentioned

VMD
GAFF
Epock
fPocket
rDock
SHAKE
GROMACS
AMBER12
LINCS
PROPKA3

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