Synthesis and structure-activity relationship of 4-(1,3-benzothiazol-2-yl)-thiophene-2-sulfonamides as cyclin-dependent kinase 5 (cdk5)/p25 inhibitors

Malmström, Jonas; Viklund, Jenny; Slivo, Can; Costa, Ana; Maudet, Mickaël; Sandelin, Catrin; Hiller, Gösta; Olsson, Lars‐Inge; Aagaard, Anna; Geschwindner, Stefan; Xue, Yafeng; Vasänge, Mervi

doi:10.1016/j.bmcl.2012.07.068

Cited by 36 publications

(22 citation statements)

References 30 publications

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“…Our results suggested that the final candidate molecules formed polar interactions (H-bonds) with Cys83 residue of the ATP-binding site of Cdk5/p25. We argued that the similar binding pattern of Cdk5 inhibitors has already been reported [ 26 , 55 , 56 ]. Additionally, our results observed that the final candidate inhibitors formed hydrogen bonds with Glu81 of the Cdk5, which has already been reported that the ATP analogue inhibitor of Cdk5 forms hydrogen bond with Glu81 of the Cdk5 [ 55 ].…”

Section: Discussionsupporting

confidence: 79%

“…Our results observed that the third polar interaction feature (hydrogen bond donor) was complemented to carbonyl group of Asp86 of Cdk5. In parallel, Malmstrom et al reported that 4-(1,3-benzothiazol-2-yl)-thiophene-2-sulfonamides forms polar interactions (H-bonds) with the carbonyl group of Asp86 of Cdk5 [ 56 ]. Our results observed that the three hydrophobic features of the selected pharmacophore established non-polar interactions with Lys33, Phe80, Ile10, and Val18.…”

Section: Discussionmentioning

confidence: 99%

“…Our results observed that the three hydrophobic features of the selected pharmacophore established non-polar interactions with Lys33, Phe80, Ile10, and Val18. Previously, hydrophobic interactions have shown to play a critical role in the pharmacological inhibition of Cdk5 [ 26 , 55 , 56 ]. Therefore, we argued that the resultant pharmacophore is a suitable choice to use as a 3D query in virtual screening of the drug-like database for the identification of candidate inhibitors of Cdk5.…”

Section: Discussionmentioning

confidence: 99%

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Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders

Zeb

Son

Yoon

et al. 2019

Computational and Structural Biotechnology Journal

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Deregulation of Cdk5 is a hallmark in neurodegenerative diseases and its complex with p25 forms Cdk5/p25, thereby causes severe neuropathological insults. Cdk5/p25 abnormally phosphorylates tau protein, and induces tau-associated neurofibrillary tangles in neurological disorders. Therefore, the pharmacological inhibition of Cdk5/p25 alleviates tau-associated neurological disorders. Herein, computational simulations probed two candidate inhibitors of Cdk5/p25. Structure-based pharmacophore investigated the essential complementary chemical features of ATP-binding site of Cdk5 in complex with roscovitine. Resultant pharmacophore harbored polar interactions with Cys83 and Asp86 residues and non-polar interactions with Ile10, Phe80, and Lys133 residues of Cdk5. The chemical space of selected pharmacophore was comprised of two hydrogen bond donors, one hydrogen bond acceptor, and three hydrophobic features. Decoy test validation of pharmacophore obtained highest Guner-Henry score (0.88) and enrichment factor score (7.23). The screening of natural product drug-like databases by validated pharmacophore retrieved 1126 compounds as candidate inhibitors of Cdk5/p25. The docking of candidate inhibitors filtered 10 molecules with docking score >80.00 and established polar and non-polar interactions with the ATP-binding site residues of Cdk5/p25. Finally, molecular dynamics simulation and binding free energy analyses identified two candidate inhibitors of Cdk5/p25. During 30 ns simulation, the candidate inhibitors established <3.0 Å root mean square deviation and stable hydrogen bond interactions with the ATP-binding site residues of Cdk5/p25. The final candidate inhibitors obtained lowest binding free energies of −122.18 kJ/mol and − 117.26 kJ/mol with Cdk5/p25. Overall, we recommend two natural product candidate inhibitors to target the pharmacological inhibition of Cdk5/p25 in tau-associated neurological disorders.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders

Zeb

Son

Yoon

et al. 2019

Computational and Structural Biotechnology Journal

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“…The halogen substituted BTAs 250(a,b) showed increased potency against cdk5, but decreased selectivity against cdk2 [284]. The structures BTA as acting as agonists or antagonists of various receptors and enzymes are shown in Fig.…”

Section: Bta Asenzyme and Receptor Agonists/antagonistsmentioning

confidence: 98%

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

Keri

Patil

et al. 2015

European Journal of Medicinal Chemistry

463

238

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“…14) are investigated for the potential treatment of AD. Medicinal chemistry was published [540] May 29, 2014). The structure of FRAX-597 ( Fig.…”

Section: Drugs Interacting With Kinases ( / = Gsk-3β and / = Pkc)mentioning

confidence: 99%

Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes. Update 2014

Froestl

Muhs

Pfeifer

2014

JAD

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Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers are very productive. The review on Drugs interacting with Enzymes was accepted in August 2012. However, this field is very dynamic. New potential targets for the treatment of Alzheimer's disease were identified. This update describes drugs interacting with 60 enzymes versus 43 enzymes in the first paper. Some compounds progressed in their development, while many others were discontinued. The present review covers the evolution of research in this field through April 2014.

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Synthesis and structure-activity relationship of 4-(1,3-benzothiazol-2-yl)-thiophene-2-sulfonamides as cyclin-dependent kinase 5 (cdk5)/p25 inhibitors

Cited by 36 publications

References 30 publications

Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders

Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes. Update 2014

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