Fragment-based discovery and optimization of BACE1 inhibitors

Madden, J. Patrick; Dod, Jenny R.; Godemann, Robert; Kraemer, Joachim; Smith, M. A.; Biniszkiewicz, Marion; Hallett, David J.; Barker, John J.; Dyekjær, Jane Dannow; Hesterkamp, Thomas

doi:10.1016/j.bmcl.2010.06.089

Cited by 43 publications

(24 citation statements)

References 7 publications

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“…Figure 3 indicated that the kinetic of lysozyme aggregation was accorded with sigmoidal increase led by a typical nucleated growth mechanism, which was described as a lag phase, a rapid exponential growth, and a final equilibrium state. The result implied the growth of cross‐amyloid fibrils, which was consistent with AFM images.…”

Section: Resultssupporting

confidence: 84%

Investigation of the interactions between aptamer and misfolded proteins: From monomer and oligomer to fibril by single‐molecule force spectroscopy

Zheng

Wang

Yang

et al. 2017

J of Molecular Recognition

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Increasing knowledge on the understanding interactions of aptamer with misfolded proteins (including monomer, oligomer, and amyloid fibril) is crucial for development of aggregation inhibitors and diagnosis of amyloid diseases. Herein, the interactions of lysozyme monomer-, oligomer-, and amyloid fibril-aptamer were investigated using single-molecule force spectroscopy. The results revealed that the aptamer screened against lysozyme monomer could also bind to oligomer and amyloid fibril, in spite of the recognition at a lower binding probability. It may be attributed to the inherent structural differences of misfolded proteins and the flexible conformation of aptamer. In addition, dynamic force spectra showed that there were similar dissociation paths in the dissociation process of lysozyme monomer-, oligomer-, and amyloid fibril-aptamer complexes. It showed that the dissociation only passed 1 energy barrier from the binding state to the detachment. However, the dynamic parameters suggested that the oligomer- and amyloid fibril-aptamer were more stable than lysozyme monomer-aptamer. The phenomena may result from the exposure of aptamer-recognized sequences on the surface and the electrostatic interactions. This work demonstrated that single-molecule force spectroscopy could be a powerful tool to study the binding behavior of the aptamer with misfolded proteins at single-molecule level, providing abundant information for researches and comprehensive applications of aptamer probes in diagnosis of amyloid diseases.

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Section: Resultssupporting

confidence: 84%

Investigation of the interactions between aptamer and misfolded proteins: From monomer and oligomer to fibril by single‐molecule force spectroscopy

Zheng

Wang

Yang

et al. 2017

J of Molecular Recognition

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“…Inhibitor 86, with a 2-aminopyridine moiety (BACE1 IC 50 = 250 µM), and 87, with an iminohydantoin moiety (BACE1 IC 50 = 7 µM) as an isothiourea analog, were designed from 85. The small molecular-sized inhibitor 88 (BACE1 IC 50 = 605 nM) was designed from 87. Researchers at Evotec reported the fragment-based BACE1 inhibitor 99 (BACE1 IC 50 = 7 µM, Figure 6D) obtained from a fragment hit compound (BACE1 IC 50 = 770 µM, the structure is not shown in this paper) by SPR [141]. The researchers at Pfizer reported a fragment-based BACE1 inhibitor 100 (NMR IC 50 = 1 µM, Figure 6D) obtained from a hit compound (NMR IC 50 = 1100 µM) with a spiropyrrolidine moiety by fragment screening using the X-ray crystallography strategy [142].…”

Section: Non-peptidic Bace1 Inhibitors Obtained By Fragment-based Drumentioning

confidence: 94%

Advances in the identification of β-secretase inhibitors

Hamada

Kiso

2013

Expert Opinion on Drug Discovery

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Many BACE1 inhibitors have been designed using X-ray crystal structure-based drug design as well as through in silico screening. Nevertheless, there are serious problems with regards to deciding the best X-ray crystal structure for designing BACE1 inhibitors through computational approaches. There are two prominent configurations of BACE1 but there is still room for improvement. Future developments may make it possible to identify BACE1 inhibitors as potential drug candidates.

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“…). Interestingly, these H‐bonds have also been reported for other inhibitors of BACE1 . In addition, Gly230 presents a weak O···N interaction (N6 (R) ‐1t/ (S) ‐1m ···O Gly230 ).…”

Section: Resultsmentioning

confidence: 53%

Molecular insight into the interaction mechanisms of amino-2H -imidazole derivatives with BACE1 protease: A QM/MM and QTAIM study

Vega-Hissi

Tosso

Enriz

et al. 2014

Int. J. Quantum Chem.

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In this study, we described quantitatively the interactions between two new amino‐2H‐imidazole inhibitors ((R)‐1t and (S)‐1m) and BACE1 using a hybrid quantum mechanics‐molecular mechanical (QM/MM) method together with a quantum theory of atoms In Molecules (QTAIM) analysis. Our computational calculations revealed that the binding affinity of these compounds is mostly related to the amino‐2H‐imidazole core, which interact tightly with the aspartate dyad of the active site. The interactions were stronger when the inhibitors presented a bulky substituent with a hydrogen bond acceptor motif pointing toward Trp76, such as the 3,5‐dimethyl‐4‐methoxyphenyl group of compound (S)‐1m. Furthermore, the QTAIM analysis revealed that many hydrophobic interactions complement cooperatively the hydrogen bond which is not present when compound (R)‐1t is bound to the enzyme. The combined QM/MM‐QTAIM analysis allows identifying the interactions that account for the activity difference between compounds, even at a nanomolar range.

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Fragment-based discovery and optimization of BACE1 inhibitors

Cited by 43 publications

References 7 publications

Investigation of the interactions between aptamer and misfolded proteins: From monomer and oligomer to fibril by single‐molecule force spectroscopy

Investigation of the interactions between aptamer and misfolded proteins: From monomer and oligomer to fibril by single‐molecule force spectroscopy

Advances in the identification of β-secretase inhibitors

Molecular insight into the interaction mechanisms of amino-2H -imidazole derivatives with BACE1 protease: A QM/MM and QTAIM study

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