Discovery of Cell-Permeable Non-Peptide Inhibitors of β-Secretase by High-Throughput Docking and Continuum Electrostatics Calculations

Huang, Danzhi; Lüthi, Urs; Kolb, Peter; Edler, Karin; Cecchini, Marco; Audetat, Stephan; Barberis, and Alcide; Caflisch, Amedeo

doi:10.1021/jm050499d

Cited by 84 publications

(69 citation statements)

References 30 publications

(70 reference statements)

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“…Conversely, we did not target the active site, and the molecules selected by docking were devoid of chemically active warheads. The finding of only one active compound out of 29 substances is in line with previous studies, which showed that candidate inhibitors predicted by docking algorithms are not necessarily active in vitro (Huang et al 2005).…”

Section: Discussionsupporting

confidence: 90%

“…Molecules with more than nine rotatable bonds were neglected. The resulting 48,026 cluster representatives were docked as in previous in silico campaigns (Huang et al 2005(Huang et al , 2006Kolb et al 2008). For each molecule docked by the program FFLD (Fragment-based Flexible Ligand Docking) (Budin et al 2001;Cecchini et al 2004), the 300 most favorable poses were clustered with the leader algorithm yielding 764,776 poses (;17 poses per compound, 44,527 compounds).…”

Section: Dockingmentioning

confidence: 99%

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A double‐headed cathepsin B inhibitor devoid of warhead

et al. 2008

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Most synthetic inhibitors of peptidases have been targeted to the active site for inhibiting catalysis through reversible competition with the substrate or by covalent modification of catalytic groups. Cathepsin B is unique among the cysteine peptidase for the presence of a flexible segment, known as the occluding loop, which can block the primed subsites of the substrate binding cleft. With the occluding loop in the open conformation cathepsin B acts as an endopeptidase, and it acts as an exopeptidase when the loop is closed. We have targeted the occluding loop of human cathepsin B at its surface, outside the catalytic center, using a high-throughput docking procedure. The aim was to identify inhibitors that would interact with the occluding loop thereby modulating enzyme activity without the help of chemical warheads against catalytic residues. From a large library of compounds, the in silico approach identified [2-[2-(2,4-dioxo-1,3-thiazolidin-3-yl)ethylamino]-2-oxoethyl] 2-(furan-2-carbonylamino) acetate, which fulfills the working hypothesis. This molecule possesses two distinct binding moieties and behaves as a reversible, double-headed competitive inhibitor of cathepsin B by excluding synthetic and protein substrates from the active center. The kinetic mechanism of inhibition suggests that the occluding loop is stabilized in its closed conformation, mainly by hydrogen bonds with the inhibitor, thus decreasing endoproteolytic activity of the enzyme. Furthermore, the dioxothiazolidine head of the compound sterically hinders binding of the C-terminal residue of substrates resulting in inhibition of the exopeptidase activity of cathepsin B in a physiopathologically relevant pH range.

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Section: Discussionsupporting

confidence: 90%

Section: Dockingmentioning

confidence: 99%

A double‐headed cathepsin B inhibitor devoid of warhead

et al. 2008

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“…12 On the contrary to free piperidine compounds 8 and 9, ureidopiperidine 11 with arylpiperazine at 3-position showed more potent activity than regioisomeric ureidopiperidine 10. Among the ureidopiperidine tested, 3,5-dichloro substituent resulted better activity than other substituents (11d-f).…”

Section: Resultsmentioning

confidence: 95%

Synthesis and Biological Activities of (4-Arylpiperazinyl)piperidines as Nonpeptide BACE 1 Inhibitors

Poojary¹,

Won²,

Suh³

et al. 2011

Bulletin of the Korean Chemical Society

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Inhibition of BACE 1 activity is considered as a promising therapeutic target for Alzheimer's Disease (AD). Synthesis and inhibitory activities of (4-arylpiperazinyl)piperidines by bioisosteric replacement of a biaryl group with an arylpiperazine as BACE 1 inhibitors are described. The resulting (4-arylpiperazinyl)piperidines represent novel nonpeptide BACE 1 inhibitors with improved in vitro potency.

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“…A similar in silico fragment-based approach had been used previously to identify novel inhibitors of the aspartic protease β-secretase [10,11], two kinases [12,13], and a flaviviral serine protease [14]. The major difference between our previous in silico screening campaigns and the one reported here is the final scoring of the poses.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Friedman

Caflisch

2009

ChemMedChem

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Plasmepsins (PMs) are essential proteases of the plasmodia parasites and are therefore promising targets for developing drugs against malaria. We have discovered six inhibitors of PM II by high‐throughput fragment‐based docking of a diversity set of ∼40 000 molecules, and consensus scoring with force field energy functions. Using the common scaffold of the three most active inhibitors (IC50=2–5 μM), another seven inhibitors were identified by substructure search. Furthermore, these 13 inhibitors belong to at least three different classes of compounds. The in silico approach was very effective since a total of 13 active compounds were discovered by testing only 59 molecules in an enzymatic assay. This hit rate is about one to two orders of magnitude higher than those reported for medium‐ and high‐throughput screening techniques in vitro. Interestingly, one of the inhibitors identified by docking was halofantrine, an antimalarial drug of unknown mechanism. Explicit water molecular dynamics simulations were used to discriminate between two putative binding modes of halofantrine in PM II.

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Discovery of Cell-Permeable Non-Peptide Inhibitors of β-Secretase by High-Throughput Docking and Continuum Electrostatics Calculations

Cited by 84 publications

References 30 publications

A double‐headed cathepsin B inhibitor devoid of warhead

A double‐headed cathepsin B inhibitor devoid of warhead

Synthesis and Biological Activities of (4-Arylpiperazinyl)piperidines as Nonpeptide BACE 1 Inhibitors

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

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