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

Ari Hardianto, Varun Khanna, Fei Liu, Shoba Ranganathan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

LanguageEnglish
Article number342
Number of pages11
JournalBMC Bioinformatics
Volume19
Issue numberSuppl. 13
DOIs
Publication statusPublished - 4 Feb 2019
EventInternational Conference on Bioinformatics (17th : 2018): bioinformatics - New Delhi, India
Duration: 26 Sep 201828 Sep 2018

Fingerprint

Protein Kinase C
Selectivity
Isoenzymes
Adenosinetriphosphate
Analogue
Proteins
Adenosine Triphosphate
Fluorine
Inhibitor
Protein Kinase
Tumor
Drugs
Tumors
Target
Sequence Analysis
Molecular Dynamics Simulation
Cyclic AMP-Dependent Protein Kinases
Promoter
Pharmaceutical Preparations
Carcinogens

Bibliographical note

Edited by Shandar Ahmad, Shoba Ranganathan, Christian Schonbach, Michael Gromiha and GPS Raghava

Keywords

  • Fluorinated balanol analogue selectivity
  • PKCϵ
  • Novel PKC isozymes
  • Unique dynamics feature
  • Molecular dynamics simulations

Cite this

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title = "Diverse dynamics features of novel protein kinase C (PKC) isozymes determine the selectivity of a fluorinated balanol analogue for PKCϵ",
abstract = "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.",
keywords = "Fluorinated balanol analogue selectivity, PKCϵ, Novel PKC isozymes, Unique dynamics feature, Molecular dynamics simulations",
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Diverse dynamics features of novel protein kinase C (PKC) isozymes determine the selectivity of a fluorinated balanol analogue for PKCϵ. / Hardianto, Ari; Khanna, Varun; Liu, Fei; Ranganathan, Shoba.

In: BMC Bioinformatics, Vol. 19, No. Suppl. 13, 342, 04.02.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Diverse dynamics features of novel protein kinase C (PKC) isozymes determine the selectivity of a fluorinated balanol analogue for PKCϵ

AU - Hardianto,Ari

AU - Khanna,Varun

AU - Liu,Fei

AU - Ranganathan,Shoba

N1 - Edited by Shandar Ahmad, Shoba Ranganathan, Christian Schonbach, Michael Gromiha and GPS Raghava

PY - 2019/2/4

Y1 - 2019/2/4

N2 - 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.

AB - 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.

KW - Fluorinated balanol analogue selectivity

KW - PKCϵ

KW - Novel PKC isozymes

KW - Unique dynamics feature

KW - Molecular dynamics simulations

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U2 - 10.1186/s12859-018-2373-1

DO - 10.1186/s12859-018-2373-1

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T2 - BMC Bioinformatics

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SN - 1471-2105

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