Prediction of relative stability between TACE/gelastatin and TACE/gelastatin hydroxamate

Ky Youb Nam, Gyoonhee Han, Hwan Mook Kim, Kyoung Tai No

Research output: Contribution to journalArticle

Abstract

A gelastatins (1), natural MMP inhibitors, and their hydroxamate analogues (2) in TACE enzyme evaluated for discovery of potent TACE inhibitors. We have employed molecular dynamics simulations to compute the relative free energy of hydration and binding to TACE for gelastatin (1) and its hydroxamate analogue (2). The relative free energy difference is directly described in this article using the free energy perturbation approach as a means to accurately predict the TACE inhibitor of gelastatin analogues. The results show that the good agreement between the experimental and theoretical relative free energies of binding, gelastatin hydroxamate (2) binds stronger to TACE by ?3.37 kcal/mol. The desolvation energy costs significantly reduced binding affinity, hydroxamate group associated with high desolvation energy formed strong favorable interactions with TACE with more than compensated for the solvation costs and therefore led to an improvement in relative binding affinity.

Original languageEnglish
Pages (from-to)3291-3296
Number of pages6
JournalBulletin of the Korean Chemical Society
Volume31
Issue number11
DOIs
Publication statusPublished - 2010 Nov 20

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Free energy
Matrix Metalloproteinase Inhibitors
Solvation
Hydration
Molecular dynamics
Costs
Computer simulation
Enzymes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)

Cite this

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title = "Prediction of relative stability between TACE/gelastatin and TACE/gelastatin hydroxamate",
abstract = "A gelastatins (1), natural MMP inhibitors, and their hydroxamate analogues (2) in TACE enzyme evaluated for discovery of potent TACE inhibitors. We have employed molecular dynamics simulations to compute the relative free energy of hydration and binding to TACE for gelastatin (1) and its hydroxamate analogue (2). The relative free energy difference is directly described in this article using the free energy perturbation approach as a means to accurately predict the TACE inhibitor of gelastatin analogues. The results show that the good agreement between the experimental and theoretical relative free energies of binding, gelastatin hydroxamate (2) binds stronger to TACE by ?3.37 kcal/mol. The desolvation energy costs significantly reduced binding affinity, hydroxamate group associated with high desolvation energy formed strong favorable interactions with TACE with more than compensated for the solvation costs and therefore led to an improvement in relative binding affinity.",
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Prediction of relative stability between TACE/gelastatin and TACE/gelastatin hydroxamate. / Nam, Ky Youb; Han, Gyoonhee; Kim, Hwan Mook; No, Kyoung Tai.

In: Bulletin of the Korean Chemical Society, Vol. 31, No. 11, 20.11.2010, p. 3291-3296.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Prediction of relative stability between TACE/gelastatin and TACE/gelastatin hydroxamate

AU - Nam, Ky Youb

AU - Han, Gyoonhee

AU - Kim, Hwan Mook

AU - No, Kyoung Tai

PY - 2010/11/20

Y1 - 2010/11/20

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AB - A gelastatins (1), natural MMP inhibitors, and their hydroxamate analogues (2) in TACE enzyme evaluated for discovery of potent TACE inhibitors. We have employed molecular dynamics simulations to compute the relative free energy of hydration and binding to TACE for gelastatin (1) and its hydroxamate analogue (2). The relative free energy difference is directly described in this article using the free energy perturbation approach as a means to accurately predict the TACE inhibitor of gelastatin analogues. The results show that the good agreement between the experimental and theoretical relative free energies of binding, gelastatin hydroxamate (2) binds stronger to TACE by ?3.37 kcal/mol. The desolvation energy costs significantly reduced binding affinity, hydroxamate group associated with high desolvation energy formed strong favorable interactions with TACE with more than compensated for the solvation costs and therefore led to an improvement in relative binding affinity.

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