Rational design of [Co(acacen)L2]+ inhibitors of protein function

Lauren M. Matosziuk, Robert J. Holbrook, Lisa M. Manus, Marie Heffern, Mark A. Ratner, Thomas J. Meade

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Cobalt(iii) Schiff base complexes, such as [Co(acacen)L2] +, inhibit the function of Zn(ii)-dependent proteins through dissociative exchange of the axial ligands with key histidine residues of the target protein. Consequently the efficacy of these compounds depends strongly on the lability of the axial ligands. A series of [Co(acacen)L2] + complexes with various axial ligands was investigated using DFT to determine the kinetics and thermodynamics of ligand exchange and hydrolysis. Results showed excellent agreement with experimental data, indicating that axial ligand lability is determined by several factors: pKa of the axial ligand, the kinetic barrier to ligand dissociation, and the relative thermodynamic stability of the complexes before and after exchange. Hammett plots were constructed to determine if the kinetics and thermodynamics of exchange can be modulated by the addition of an electron-withdrawing group (EWG) to either the axial ligand itself or to the equatorial acacen ligand. Results predict that addition of an EWG to the axial ligand will shift the kinetics and thermodynamics so as to promote axial ligand exchange, while addition of an EWG to acacen will decrease axial ligand lability. These investigations will aid in the design of the next generation of [Co(acacen)L2]2+, allowing researchers to develop new, more effective inhibitors.

Original languageEnglish (US)
Pages (from-to)4002-4012
Number of pages11
JournalDalton Transactions
Volume42
Issue number11
DOIs
StatePublished - Mar 21 2013
Externally publishedYes

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Ligands
Proteins
Kinetics
Thermodynamics
Electrons
Schiff Bases
Cobalt
Histidine
Discrete Fourier transforms
Hydrolysis
Thermodynamic stability

ASJC Scopus subject areas

  • Inorganic Chemistry

Cite this

Matosziuk, L. M., Holbrook, R. J., Manus, L. M., Heffern, M., Ratner, M. A., & Meade, T. J. (2013). Rational design of [Co(acacen)L2]+ inhibitors of protein function. Dalton Transactions, 42(11), 4002-4012. https://doi.org/10.1039/c2dt32565a

Rational design of [Co(acacen)L2]+ inhibitors of protein function. / Matosziuk, Lauren M.; Holbrook, Robert J.; Manus, Lisa M.; Heffern, Marie; Ratner, Mark A.; Meade, Thomas J.

In: Dalton Transactions, Vol. 42, No. 11, 21.03.2013, p. 4002-4012.

Research output: Contribution to journalArticle

Matosziuk, LM, Holbrook, RJ, Manus, LM, Heffern, M, Ratner, MA & Meade, TJ 2013, 'Rational design of [Co(acacen)L2]+ inhibitors of protein function', Dalton Transactions, vol. 42, no. 11, pp. 4002-4012. https://doi.org/10.1039/c2dt32565a
Matosziuk LM, Holbrook RJ, Manus LM, Heffern M, Ratner MA, Meade TJ. Rational design of [Co(acacen)L2]+ inhibitors of protein function. Dalton Transactions. 2013 Mar 21;42(11):4002-4012. https://doi.org/10.1039/c2dt32565a
Matosziuk, Lauren M. ; Holbrook, Robert J. ; Manus, Lisa M. ; Heffern, Marie ; Ratner, Mark A. ; Meade, Thomas J. / Rational design of [Co(acacen)L2]+ inhibitors of protein function. In: Dalton Transactions. 2013 ; Vol. 42, No. 11. pp. 4002-4012.
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