Molecular modelling of human DT-Diaphorase for enzyme-directed bioreductive drug design

S. W. Doughty, R. M. Phillips

Research output: Contribution to journalConference article

4 Citations (Scopus)

Abstract

The enzyme DT-Diaphorase (NAD(P)H:quinone acceptor oxidoreductase, EC 1.6.99.2.; DTD) has been recognised as a good target for enzyme-directed bioreductive drug development. This is due to elevated levels of enzyme activity in several human tumour types and its role in the bioreductive activation of several quinone-based anti-cancer drugs. Bioreductive drugs are designed to exploit one of the features of solid tumours, namely tumour hypoxia. However, selectivity of bioreductive drugs is not only governed by oxygen levels, but also by the levels of the enzymes catalysing bioreductive activation, leading to the concept of "enzyme-directed bioreductive drug development" introduced by Workman and Walton in 1990. This concept requires the identification of tumours within a patient that have elevated levels of enzyme activity (enzyme profiling) and treating the patient with drugs activated by such enzymes. DTD has been singled out as a particularly good candidate for such targeting. In order to rationalise the design of drugs to target DTD, molecular modelling techniques have been employed. The human DTD three-dimensional structure has been modelled with homology to the known rat DTD structure (about 85% identity) and the model refined using energy minimisation. Drug-binding orientations have been determined and molecular dynamics simulations performed. Using data from a series of quinone based compounds with a broad range of substrate specificity we examine drug-enzyme interactions and suggest how DTD substrate specificity might be further optimised.

Original languageEnglish
Pages (from-to)209-214
Number of pages6
JournalMolecular Simulation
Volume24
Issue number4-6
DOIs
Publication statusPublished - Apr 2000
Externally publishedYes
EventProceedings of the Virtual Conference Applications and Molecular Simulation in the Physical and Biological Sciences -
Duration: 19 Apr 19994 May 1999

Fingerprint

NAD(P)H Dehydrogenase (Quinone)
Molecular Modeling
Drug Design
Molecular modeling
enzymes
Drugs
Enzymes
drugs
Tumors
Pharmaceutical Preparations
Tumor
quinones
tumors
Enzyme activity
enzyme activity
Chemical activation
Specificity
Activation
Substrate
activation

Cite this

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title = "Molecular modelling of human DT-Diaphorase for enzyme-directed bioreductive drug design",
abstract = "The enzyme DT-Diaphorase (NAD(P)H:quinone acceptor oxidoreductase, EC 1.6.99.2.; DTD) has been recognised as a good target for enzyme-directed bioreductive drug development. This is due to elevated levels of enzyme activity in several human tumour types and its role in the bioreductive activation of several quinone-based anti-cancer drugs. Bioreductive drugs are designed to exploit one of the features of solid tumours, namely tumour hypoxia. However, selectivity of bioreductive drugs is not only governed by oxygen levels, but also by the levels of the enzymes catalysing bioreductive activation, leading to the concept of {"}enzyme-directed bioreductive drug development{"} introduced by Workman and Walton in 1990. This concept requires the identification of tumours within a patient that have elevated levels of enzyme activity (enzyme profiling) and treating the patient with drugs activated by such enzymes. DTD has been singled out as a particularly good candidate for such targeting. In order to rationalise the design of drugs to target DTD, molecular modelling techniques have been employed. The human DTD three-dimensional structure has been modelled with homology to the known rat DTD structure (about 85{\%} identity) and the model refined using energy minimisation. Drug-binding orientations have been determined and molecular dynamics simulations performed. Using data from a series of quinone based compounds with a broad range of substrate specificity we examine drug-enzyme interactions and suggest how DTD substrate specificity might be further optimised.",
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Molecular modelling of human DT-Diaphorase for enzyme-directed bioreductive drug design. / Doughty, S. W.; Phillips, R. M.

In: Molecular Simulation, Vol. 24, No. 4-6, 04.2000, p. 209-214.

Research output: Contribution to journalConference article

TY - JOUR

T1 - Molecular modelling of human DT-Diaphorase for enzyme-directed bioreductive drug design

AU - Doughty, S. W.

AU - Phillips, R. M.

PY - 2000/4

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N2 - The enzyme DT-Diaphorase (NAD(P)H:quinone acceptor oxidoreductase, EC 1.6.99.2.; DTD) has been recognised as a good target for enzyme-directed bioreductive drug development. This is due to elevated levels of enzyme activity in several human tumour types and its role in the bioreductive activation of several quinone-based anti-cancer drugs. Bioreductive drugs are designed to exploit one of the features of solid tumours, namely tumour hypoxia. However, selectivity of bioreductive drugs is not only governed by oxygen levels, but also by the levels of the enzymes catalysing bioreductive activation, leading to the concept of "enzyme-directed bioreductive drug development" introduced by Workman and Walton in 1990. This concept requires the identification of tumours within a patient that have elevated levels of enzyme activity (enzyme profiling) and treating the patient with drugs activated by such enzymes. DTD has been singled out as a particularly good candidate for such targeting. In order to rationalise the design of drugs to target DTD, molecular modelling techniques have been employed. The human DTD three-dimensional structure has been modelled with homology to the known rat DTD structure (about 85% identity) and the model refined using energy minimisation. Drug-binding orientations have been determined and molecular dynamics simulations performed. Using data from a series of quinone based compounds with a broad range of substrate specificity we examine drug-enzyme interactions and suggest how DTD substrate specificity might be further optimised.

AB - The enzyme DT-Diaphorase (NAD(P)H:quinone acceptor oxidoreductase, EC 1.6.99.2.; DTD) has been recognised as a good target for enzyme-directed bioreductive drug development. This is due to elevated levels of enzyme activity in several human tumour types and its role in the bioreductive activation of several quinone-based anti-cancer drugs. Bioreductive drugs are designed to exploit one of the features of solid tumours, namely tumour hypoxia. However, selectivity of bioreductive drugs is not only governed by oxygen levels, but also by the levels of the enzymes catalysing bioreductive activation, leading to the concept of "enzyme-directed bioreductive drug development" introduced by Workman and Walton in 1990. This concept requires the identification of tumours within a patient that have elevated levels of enzyme activity (enzyme profiling) and treating the patient with drugs activated by such enzymes. DTD has been singled out as a particularly good candidate for such targeting. In order to rationalise the design of drugs to target DTD, molecular modelling techniques have been employed. The human DTD three-dimensional structure has been modelled with homology to the known rat DTD structure (about 85% identity) and the model refined using energy minimisation. Drug-binding orientations have been determined and molecular dynamics simulations performed. Using data from a series of quinone based compounds with a broad range of substrate specificity we examine drug-enzyme interactions and suggest how DTD substrate specificity might be further optimised.

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