Multitargeting or polypharmacological approaches, looking for single chemical entities retaining the ability to bind two or more molecular targets, are a potentially powerful strategy to fight complex, multifactorial pathologies. Unfortunately, the search for multiligand agents is challenging because only a small subset of molecules contained in molecular databases are bioactive and even fewer are active on a preselected set of multiple targets. However, collections of natural compounds feature a significantly higher fraction of bioactive molecules than synthetic ones. In this view, we searched our library of 1175 natural compounds from marine sources for molecules including a 2-aminoimidazole+aromatic group motif, found in known compounds active on single relevant targets for Alzheimer's disease (AD). This identified two molecules, a pseudozoanthoxanthin (1) and a bromo-pyrrole alkaloid (2), which were predicted by a computational approach to possess interesting multitarget profiles on AD target proteins. Biochemical assays experimentally confirmed their biological activities. The two compounds inhibit acetylcholinesterase, butyrylcholinesterase, and beta-secretase enzymes in high-to submicromolar range. They are also able to prevent and revert beta-amyloid (A beta) aggregation of both A beta(1-40) and A beta(1-42) peptides, with 1 being more active than 2. Preliminary in vivo studies suggest that compound 1 is able to restore cholinergic corticohippocampal functional connectivity.
In Silico Identification and Experimental Validation of Novel Anti-Alzheimer's Multitargeted Ligands from a Marine Source Featuring a "2-Aminoimidazole plus Aromatic Group" Scaffold
Vitale RM;Vassalli M;Carbone M;Ciavatta ML;Mollo E;Gavagnin Capoggiani M;Amodeo P
2018
Abstract
Multitargeting or polypharmacological approaches, looking for single chemical entities retaining the ability to bind two or more molecular targets, are a potentially powerful strategy to fight complex, multifactorial pathologies. Unfortunately, the search for multiligand agents is challenging because only a small subset of molecules contained in molecular databases are bioactive and even fewer are active on a preselected set of multiple targets. However, collections of natural compounds feature a significantly higher fraction of bioactive molecules than synthetic ones. In this view, we searched our library of 1175 natural compounds from marine sources for molecules including a 2-aminoimidazole+aromatic group motif, found in known compounds active on single relevant targets for Alzheimer's disease (AD). This identified two molecules, a pseudozoanthoxanthin (1) and a bromo-pyrrole alkaloid (2), which were predicted by a computational approach to possess interesting multitarget profiles on AD target proteins. Biochemical assays experimentally confirmed their biological activities. The two compounds inhibit acetylcholinesterase, butyrylcholinesterase, and beta-secretase enzymes in high-to submicromolar range. They are also able to prevent and revert beta-amyloid (A beta) aggregation of both A beta(1-40) and A beta(1-42) peptides, with 1 being more active than 2. Preliminary in vivo studies suggest that compound 1 is able to restore cholinergic corticohippocampal functional connectivity.File | Dimensione | Formato | |
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Vitale_et_al_2018_ACS_Chem_Neurosci_editoriale_rid.pdf
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Descrizione: In Silico Identification and Experimental Validation of Novel Anti- Alzheimer’s Multitargeted Ligands from a Marine Source Featuring a “2-Aminoimidazole plus Aromatic Group” Scaffold
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Descrizione: In Silico Identification and Experimental Validation of Novel Anti- Alzheimer’s Multitargeted Ligands from a Marine Source Featuring a “2-Aminoimidazole plus Aromatic Group” Scaffold
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