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 language | English |
|---|---|
| Pages (from-to) | 209-214 |
| Number of pages | 6 |
| Journal | Molecular Simulation |
| Volume | 24 |
| Issue number | 4-6 |
| DOIs | |
| Publication status | Published - Apr 2000 |
| Externally published | Yes |
| Event | Proceedings of the Virtual Conference Applications and Molecular Simulation in the Physical and Biological Sciences - Duration: 19 Apr 1999 → 4 May 1999 |
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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 journal › Conference 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
Y1 - 2000/4
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.
KW - Bioreduction
KW - DT-Diaphorase
KW - Flavoprotein
KW - Molecular model
UR - http://www.scopus.com/inward/record.url?scp=0001120455&partnerID=8YFLogxK
U2 - 10.1080/08927020008022371
DO - 10.1080/08927020008022371
M3 - Conference article
VL - 24
SP - 209
EP - 214
JO - Molecular Simulation
JF - Molecular Simulation
SN - 0892-7022
IS - 4-6
ER -