Divergent response of homologous ATP sites to stereospecific ligand fluorination for selectivity enhancement

Patel, Ayush; Hardianto, Ari; Ranganathan, Shoba; Liu, Fei

doi:10.1039/c7ob00129k

Cited by 11 publications

(35 citation statements)

References 31 publications

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“…Therefore, we elucidate interactions made by 1c in every nPKC isozyme, particularly interactions between the azepane ring and the ribose subsite. This selection is based on an assumption that the azepane ring is the central moiety that connects the benzamide and the benzophenone moieties [3]. Furthermore, the azepane ring is the moiety where the fluorine substituent is incorporated at the C5(S) position.…”

Section: Dynamics Feature Of Novel Pkc Isozymesmentioning

confidence: 99%

“…The benzamide and azepane moieties occupy the adenine and ribose subsites, respectively, whereas the benzophenone moiety resides in the triphosphate subsites. In balanol structure, the azepane ring is in a central position [3] that connects the benzamide and benzophenone moieties. Amide and ester linkages respectively join the benzamide and benzophenone moieties to the azepane.…”

Section: Introductionmentioning

confidence: 99%

“…In a recent study [3], for the first time, we carried out stereospecific single and multiple fluorinations on the azepane moiety of balanol. The effect of azepane fluorination on protein selectivity was evaluated by binding affinity measurement of balanol and the fluorinated balanol analogues (altogether referred as balanoids) to novel PKC (nPKC) isozymes and PKA [3]. We found that the fluorinations on balanol produce various responses to kinases studied, where the C5(S)-fluorinated analogue or 1c ( Fig.…”

Section: Introductionmentioning

confidence: 99%

“…1c) over other nPKC isozymes and PKA. This stereospecific fluorination offers ligand-enzyme selectivity in highly homologous ATP sites [3].…”

Section: Introductionmentioning

confidence: 99%

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Diverse dynamics features of novel protein kinase C (PKC) isozymes determine the selectivity of a fluorinated balanol analogue for PKCε

et al. 2019

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Background: (−)-Balanol is an ATP-mimicking inhibitor that non-selectively targets protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA). While PKA constantly shows tumor promoting activities, PKC isozymes can ambiguously be tumor promoters or suppressors. In particular, PKCε is frequently implicated in tumorigenesis and a potential target for anticancer drugs. We recently reported that the C5(S)-fluorinated balanol analogue (balanoid 1c) had improved binding affinity and selectivity for PKCε but not to the other novel PKC isozymes, which share a highly similar ATP site. The underlying basis for this fluorine-based selectivity is not entirely comprehended and needs to be investigated further for the development of ATP mimic inhibitors specific for PKCε. Results: Using molecular dynamics (MD) simulations assisted by homology modelling and sequence analysis, we have studied the fluorine-based selectivity in the highly similar ATP sites of novel PKC (nPKC) isozymes. The study suggests that every nPKC isozyme has different dynamics behaviour in both apo and 1c-bound forms. Interestingly, the apo form of PKCε, where 1c binds strongly, shows the highest degree of flexibility which dramatically decreases after binding 1c. Conclusions: For the first time to the best of our knowledge, we found that the origin of 1c selectivity for PKCε comes from the unique dynamics feature of each PKC isozyme. Fluorine conformational control in 1c can synergize with and lock down the dynamics of PKCε, which optimize binding interactions with the ATP site residues of the enzyme, particularly the invariant Lys437. This finding has implications for further rational design of balanol-based PKCε inhibitors for cancer drug development.

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Section: Dynamics Feature Of Novel Pkc Isozymesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…1c) over other nPKC isozymes and PKA. This stereospecific fluorination offers ligand-enzyme selectivity in highly homologous ATP sites [3].…”

Section: Introductionmentioning

confidence: 99%

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Diverse dynamics features of novel protein kinase C (PKC) isozymes determine the selectivity of a fluorinated balanol analogue for PKCε

et al. 2019

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“…Due to the importance of azepanes in medicinal chemistry, and the possibility to modulate the properties of these compounds by introducing fluorinated groups, the development of methods to access α‐fluoroalkylated azepanes I is of interest (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 2‐Fluoroalkyl 4‐Substituted Azepanes

et al. 2019

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Synthesis of di‐ and tri‐substituted fluoroalkylated azepanes was achieved by ring expansion of pyrrolidines via a regioselective attack of nucleophiles on a bicyclic azetidinium intermediate. A broad scope of azepanes, substituted at C4 and bearing a α‐trifluoromethyl, α‐difluoromethyl or α‐perfluorobutyl group, can be synthesized by this method by using a wide variety of nucleophiles.

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Pharmacophore modeling, docking and molecular dynamics simulation for identification of novel human protein kinase C beta (PKCβ) inhibitors

et al. 2022

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Protein kinase Cβ (PKCβ) is considered as an attractive molecular target for the treatment of COVID-19-related acute respiratory distress syndrome (ARDS). Several classes of inhibitors have been already identified. In this article, we developed and validated ligand-based PKCβ pharmacophore models based on the chemical structures of the known inhibitors. The most accurate pharmacophore model, which correctly predicted more than 70% active compounds of test set, included three aromatic pharmacophore features without vectors, one hydrogen bond acceptor pharmacophore feature, one hydrophobic pharmacophore feature and 158 excluded volumes. This pharmacophore model was used for virtual screening of compound collection in order to identify novel potent PKCβ inhibitors. Also, molecular docking of compound collection was performed and 28 compounds which were selected simultaneously by two approaches as top-scored were proposed for further biological research. Supplementary Information The online version contains supplementary material available at 10.1007/s11224-022-02075-y.

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Divergent response of homologous ATP sites to stereospecific ligand fluorination for selectivity enhancement

Cited by 11 publications

References 31 publications

Diverse dynamics features of novel protein kinase C (PKC) isozymes determine the selectivity of a fluorinated balanol analogue for PKCε

Diverse dynamics features of novel protein kinase C (PKC) isozymes determine the selectivity of a fluorinated balanol analogue for PKCε

Synthesis of 2‐Fluoroalkyl 4‐Substituted Azepanes

Pharmacophore modeling, docking and molecular dynamics simulation for identification of novel human protein kinase C beta (PKCβ) inhibitors

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