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Bioorganic & medicinal chemistry letters (1)
Journal of biomolecular screening (1)
Molecules (Basel, Switzerland) (1)
Fokin, Valery V. (2)
Jiaranaikulwanitch, Jutamas (2)
Vajragupta, Opa (2)
Boonyarat, Chantana (1)
Govitrapong, Piyarat (1)
OLSON, ARTHUR J. (1)
TALLEY, TODD T. (1)
TAYLOR, PALMER W. (1)
UTSINTONG, MALEERUK (1)
VAJRAGUPTA, OPA (1)
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From BACE1 Inhibitor to Multifunctionality of Tryptoline and Tryptamine Triazole Derivatives for Alzheimer’s Disease
Fokin, Valery V.
Molecules (Basel, Switzerland)
Efforts to discover new drugs for Alzheimer’s disease emphasizing multiple targets was conducted seeking to inhibit amyloid oligomer formation and to prevent radical formation. The tryptoline and tryptamine cores of BACE1 inhibitors previously identified by virtual screening were modified in silico for additional modes of action. These core structures were readily linked to different side chains using 1,2,3-triazole rings as bridges by copper catalyzed azide-alkyne cycloaddition reactions. Three compounds among the sixteen designed compounds exerted multifunctional activities including β-secretase inhibitory action, anti-amyloid aggregation, metal chelating and antioxidant effects at micromolar levels. The neuroprotective effects of the multifunctional compounds 6h, 12c and 12h on Aβ1–42 induced neuronal cell death at 1 μM were significantly greater than those of the potent single target compound, BACE1 inhibitor IV and were comparable to curcumin. The observed synergistic effect resulting from the reduction of the Aβ1–42 neurotoxicity cascade substantiates the validity of our multifunctional strategy in drug discovery for Alzheimer’s disease.
multifunction drugs; BACE1 inhibitor; anti-amyloid aggregation; chelator; antioxidant; neuroprotection
Triazolyl tryptoline derivatives as β-secretase inhibitors
Fokin, Valery V.
Bioorganic & medicinal chemistry letters
Tryptoline, a core structure of ochrolifuanine E, which is a hit compound from virtual screening of the Thai herbal database against BACE1 was used as a scaffold for the design of BACE1 inhibitors. The tryptoline was linked with different side chains by 1,2,3-triazole ring readily synthesized by catalytic azide-alkyne cycloaddition reactions. Twenty two triazolyl tryptoline derivatives were synthesized and screened for the inhibitory action against BACE1. JJCA-140 was the most potent inhibitor (IC50 = 1.49 μM) and was 100 times more selective for BACE1 than for Cat-D.
BACE1; BACE1 inhibitor; JJCA-140; Tryptoline; Docking; Binding mode; Enzyme assay; Cathepsin-D
Virtual Screening Against α-Cobratoxin
TALLEY, TODD T.
TAYLOR, PALMER W.
OLSON, ARTHUR J.
Journal of biomolecular screening
α-Cobratoxin (Cbtx), the neurotoxin isolated from the venom of the Thai cobra Naja kaouthia, causes paralysis by preventing acetylcholine (ACh) binding to nicotinic acetylcholine receptors (nAChRs). In the current study, the region of the Cbtx molecule that is directly involved in binding to nAChRs is used as the target for anticobratoxin drug design. The crystal structure (1YI5) of Cbtx in complex with the acetylcholine binding protein (AChBP), a soluble homolog of the extracellular binding domain of nAChRs, was selected to prepare an α-cobratoxin active binding site for docking. The amino acid residues (Ser182-Tyr192) of the AChBP structure, the binding site of Cbtx, were used as the positive control to validate the prepared Cbtx active binding site (root mean square deviation < 1.2 Å). Virtual screening of the National Cancer Institute diversity set, a library of 1990 compounds with nonredundant pharmacophore profiles, using AutoDock against the Cbtx active site, revealed 39 potential inhibitor candidates. The adapted in vitro radioligand competition assays using [3H]epibatidine and [125I]bungarotoxin against the AChBPs from the marine species, Aplysia californica (Ac), and from the freshwater snails, Lymnaea stagnalis (Ls) and Bolinus truncates (Bt), revealed 4 compounds from the list of inhibitor candidates that had micromolar to nanomolar interferences for the toxin binding to AChBPs. Three hits (NSC42258, NSC121865, and NSC134754) can prolong the survival time of the mice if administered 30 min before injection with Cbtx, but only NSC121865 and NSC134754 can prolong the survival time if injected immediately after injection with Cbtx. These inhibitors serve as novel templates/scaffolds for the development of more potent and specific anticobratoxin.
α-cobratoxin; virtual screening; docking; neurotoxin; nicotinic acetylcholine receptor
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