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2001 | 48 | 4 | 903-916
Article title

Computer modeling studies of the structural role of NADPH binding to active site mutants of human dihydrofolate reductase in complex with piritrexim.

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EN
Abstracts
EN
Dihydrofolate reductase (DHFR, EC 1.5.1.3) is one of the enzymes active in the folate cycle which plays an important role in DNA synthesis. Inhibition of DHFR is a key element in the treatment of many diseases, including cancer and AIDS related infections. A search for new selective inhibitors is motivated by the resistance to common drugs observed in the course of treatment. In this paper, results of a detailed computer analysis of human DHFR interactions with the lipophilic inhibitor piritrexim (PTX) are presented. It was found that the NADPH cofactor contributes 30% of the total PTX-enzyme interaction energy. Substitution of the highly conserved Glu30 with alanine does not lead to the release of the inhibitor from the hDHFR pocket. The important L22F point mutation does affect PTX orientation but does not change the binding energy. Simulations of the dynamics of binary hDHFR-TX complexes were performed with the use of Extensible Systematic Force Field (ESFF) and the results indicate structural changes in the enzyme induced by NADPH binding.
Publisher

Year
Volume
48
Issue
4
Pages
903-916
Physical description
Dates
published
2001
received
2001-11-19
accepted
2001-12-03
Contributors
  • Institute of Physics, Nicholas Copernicus University, Toruń, Poland
author
  • Hauptman-Woodward Medical Research Institute, Buffalo, U.S.A.
  • Institute of Chemistry, Nicholas Copernicus University, Toruń, Poland
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Document Type
Publication order reference
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YADDA identifier
bwmeta1.element.bwnjournal-article-abpv48i4p903kz
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