Design, synthesis, and testing of an 6-O-linked series of benzimidazole based inhibitors of CDK5/p25

Jain, Prashi; Flaherty, Patrick; Yi, Shuyan; Chopra, Ishveen; Bleasdell, Gwenyth; Lipay, Josh; Ferandin, Yoan; Meijer, Laurent; Madura, Jeffry D.

doi:10.1016/j.bmc.2010.11.022

Cited by 20 publications

(18 citation statements)

References 86 publications

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“…We used 1 and 4 as the standards for the assay validation and found that both compounds showed sub-micromolar activities for CDK5/p25 as reported earlier, 19,21 but showed selectivity towards CDK2/E.…”

Section: Resultsmentioning

confidence: 86%

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Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening

Chatterjee

Cutler

Doerksen

et al. 2014

Bioorganic & Medicinal Chemistry

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Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer’s disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening work-flow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[3,2-c]quinolin-4(5H)-one inhibitor (10) with ligand efficiency (LE) of 0.3 was identified as the lead molecule. Further SAR optimization led to the discovery of several low micromolar inhibitors with good selectivity. The research represents a new class of potent ATP non-competitive CDK5/p25 inhibitors with good CDK2/E selectivity.

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Section: Resultsmentioning

confidence: 86%

“…Even with the availability of the crystal structures, to-date only a few groups have utilized structure-based design using simple docking protocols to identify leads. 21–23 …”

Section: Introductionmentioning

confidence: 99%

Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening

Chatterjee

Cutler

Doerksen

et al. 2014

Bioorganic & Medicinal Chemistry

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“…Recently, many researchers designed and synthesized several kinds of inhibitors of CDK5/p25 including purine [13], bisindoles [12,14], aloisines [15], quinolin-one [16], amino-thiazoles [17], paullones [18,19] and other typical inhibitors [1]. Theoretically, Haq et, al.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the CDK5/p25 complex has become an attractive pharmacological target. The design of novel CDK5/p25 inhibitors attracts much interest in recent years [1,[10][11][12][13][14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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Binding mechanism of CDK5 with roscovitine derivatives based on molecular dynamics simulations and MM/PBSA methods

Keke

Wang

Yang

et al. 2016

Journal of Molecular Graphics and Modelling

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Roscovitine derivatives are potent inhibitors of cyclin-dependent kinase 5 (CDK5), but they exhibit different activities, which has not been understood clearly up to now. On the other hand, the task of drug design is difficult because of the fuzzy binding mechanism. In this context, the methods of molecular docking, molecular dynamics (MD) simulation, and binding free energy analysis are applied to investigate and reveal the detailed binding mechanism of four roscovitine derivatives with CDK5. The electrostatic and van der Waals interactions of the four inhibitors with CDK5 are analyzed and discussed. The calculated binding free energies in terms of MM-PBSA method are consistent with experimental ranking of inhibitor effectiveness for the four inhibitors. The hydrogen bonds of the inhibitors with Cys83 and Lys33 can stabilize the inhibitors in binding sites. The van der Waals interactions, especially the pivotal contacts with Ile10 and Leu133 have larger contributions to the binding free energy and play critical roles in distinguishing the variant bioactivity of four inhibitors. In terms of binding mechanism of the four inhibitors with CDK5 and energy contribution of fragments of each inhibitor, two new CDK5 inhibitors are designed and have stronger inhibitory potency.

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Substituent Orchestration in Dimethylquinoxaline Derivatives: A Tool for Fishing Out Appropriate CDK5 Inhibitors as Potential Therapeutics for Alzheimer's

Jain

Gupta

Karthikeyan

et al. 2022

Chemistry & Biodiversity

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A set of new heterocyclic analogs (Compounds I-IX), comprising of 6,7 dimethyl Quinoxalines were found to be active against the receptor GSK3β (Compounds IV-V) (Chem. Biodiversity 2021, 18, e2100364). In an effort to modulate effective CDK5 inhibitors herein our hypothesis underpinned to fish out an appropriate derivative from the same quinoxaline series, as these two targets GSK3β and CDK5 shared structural resemblance with each other. Aligned to the goal we have synthesized Compounds I-IX, characterized them using a combination of spectroscopic techniques and evaluated their activities against CDK5. Our analysis reflected that the adjacently located alkoxy/hydroxy functionality derivatives namely Compounds III and VI, to be the most potent (micromolar) amongst others in the series, backed by Density Functional Theory (DFT) calculations and molecular modelling studies. Also, the efficacy of the Compounds I-IX, were monitored in few other members of the CMGC family namely DYRK1A, CLK1and CK1δ that have been known to be directly involved in hyperphosphorylation of Tau. But unfortunately in none of the targets, our quinoxaline series were active. In a nut shell further optimisation of these intelligent nucleus, would not only lead to the discovery of novel pharmacophores, but also marked selectivity against a pool of kinases, thereby implementing a distinct roadmap towards the design of potential therapeutics against Alzheimer's.

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Design, synthesis, and testing of an 6-O-linked series of benzimidazole based inhibitors of CDK5/p25

Cited by 20 publications

References 86 publications

Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening

Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening

Binding mechanism of CDK5 with roscovitine derivatives based on molecular dynamics simulations and MM/PBSA methods

Substituent Orchestration in Dimethylquinoxaline Derivatives: A Tool for Fishing Out Appropriate CDK5 Inhibitors as Potential Therapeutics for Alzheimer's

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