Dataset Information

Pyridinylimidazoles as GSK3? Inhibitors: The Impact of Tautomerism on Compound Activity via Water Networks.

ABSTRACT: Glycogen synthase kinase-3? (GSK3?) is involved in many pathological conditions and represents an attractive drug target. We previously reported dual GSK3?/p38? mitogen-activated protein kinase inhibitors and identified N-(4-(4-(4-fluorophenyl)-2-methyl-1H-imidazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide (1) as a potent dual inhibitor of both target kinases. In this study, we aimed to design selective GSK3? inhibitors based on our pyridinylimidazole scaffold. Our efforts resulted in several novel and potent GSK3? inhibitors with IC50 values in the low nanomolar range. 5-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-4-cyclopropyl-1H-imidazole-2-carboxamide (6g) displayed very good kinase selectivity as well as metabolical stability and inhibited GSK3? activity in neuronal SH-SY5Y cells. Interestingly, we observed the importance of the 2-methylimidazole's tautomeric state for the compound activity. Finally, we reveal how this crucial tautomerism effect is surmounted by imidazole-2-carboxamides, which are able to stabilize the binding via enhanced water network interactions, regardless of their tautomeric state.

SUBMITTER: Heider F

PROVIDER: S-EPMC6792175 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Pyridinylimidazoles as GSK3β Inhibitors: The Impact of Tautomerism on Compound Activity via Water Networks.

Heider Fabian F Pantsar Tatu T Kudolo Mark M Ansideri Francesco F De Simone Angela A Pruccoli Letizia L Schneider Taiane T Goettert Marcia Inês MI Tarozzi Andrea A Andrisano Vincenza V Laufer Stefan A SA Koch Pierre P

ACS medicinal chemistry letters 20190826 10

Glycogen synthase kinase-3β (GSK3β) is involved in many pathological conditions and represents an attractive drug target. We previously reported dual GSK3β/p38α mitogen-activated protein kinase inhibitors and identified N-(4-(4-(4-fluorophenyl)-2-methyl-1H-imidazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide (1) as a potent dual inhibitor of both target kinases. In this study, we aimed to design selective GSK3β inhibitors based on our pyridinylimidazole scaffold. Our efforts r ...[more]

PMID: 31620226

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Project description:Alzheimer's disease (AD) is the most common cause of dementia, affecting approximately 35 million people worldwide. The current treatment options for people with AD consist of drugs designed to slow the rate of decline in memory and cognition, but these treatments are not curative, and patients eventually suffer complete cognitive injury. With the substantial amounts of published data on targets for this disease, we proposed that machine learning software could be used to find novel small-molecule treatments that can supplement the AD drugs currently on the market. In order to do this, we used publicly available data in ChEMBL to build and validate Bayesian machine learning models for AD target proteins. The first AD target that we have addressed with this method is the serine-threonine kinase glycogen synthase kinase 3 beta (GSK3?), which is a proline-directed serine-threonine kinase that phosphorylates the microtubule-stabilizing protein tau. This phosphorylation prompts tau to dissociate from the microtubule and form insoluble oligomers called paired helical filaments, which are one of the components of the neurofibrillary tangles found in AD brains. Using our Bayesian machine learning model for GSK3? consisting of 2368 molecules, this model produced a five-fold cross validation ROC of 0.905. This model was also used for virtual screening of large libraries of FDA-approved drugs and clinical candidates. Subsequent testing of selected compounds revealed a selective small-molecule inhibitor, ruboxistaurin, with activity against GSK3? (avg IC50 = 97.3 nM) and GSK3? (IC50 = 695.9 nM). Several other structurally diverse inhibitors were also identified. We are now applying this machine learning approach to additional AD targets to identify approved drugs or clinical trial candidates that can be repurposed as AD therapeutics. This represents a viable approach to accelerate drug discovery and do so at a fraction of the cost of traditional high throughput screening.

Dataset Information

Pyridinylimidazoles as GSK3? Inhibitors: The Impact of Tautomerism on Compound Activity via Water Networks.

Publications

Pyridinylimidazoles as GSK3β Inhibitors: The Impact of Tautomerism on Compound Activity via Water Networks.

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