Dihydrofolate reductase

a potential drug target in trypanosomes and leishmania

Fabio Zuccotto, Andrew C. R. Martin, Roman A. Laskowski, Janet M. Thornton, Ian H. Gilbert

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Dihydrofolate reductase has successfully been used as a drug target in the area of anti-cancer, anti-bacterial and anti-malarial chemotherapy. Little has been done to evaluate it as a drug target for treatment of the trypanosomiases and leishmaniasis. A crystal structure of Leishmania major dihydrofolate reductase has been published. In this paper, we describe the modelling of Trypanosoma cruzi and Trypanosoma brucei dihydrofolate reductases based on this crystal structure. These structures and models have been used in the comparison of protozoan, bacterial and human enzymes in order to highlight the different features that can be used in the design of selective anti-protozoan agents. Comparison has been made between residues present in the active site, the accessibility of these residues, charge distribution in the active site, and the shape and size of the active sites. Whilst there is a high degree of similarity between protozoan, human and bacterial dihydrofolate reductase active sites, there are differences that provide potential for selective drug design. In particular, we have identified a set of residues which may be important for selective drug design and identified a larger binding pocket in the protozoan than the human and bacterial enzymes.

Original languageEnglish
Pages (from-to)241-257
Number of pages17
JournalJournal of Computer-Aided Molecular Design
Volume12
Issue number3
DOIs
Publication statusPublished - May 1998

Keywords

  • Comparative molecular modelling
  • Dihydrofolate reductase
  • Drug design
  • Protein structure

Cite this

Zuccotto, Fabio ; Martin, Andrew C. R. ; Laskowski, Roman A. ; Thornton, Janet M. ; Gilbert, Ian H. . / Dihydrofolate reductase : a potential drug target in trypanosomes and leishmania. In: Journal of Computer-Aided Molecular Design. 1998 ; Vol. 12, No. 3. pp. 241-257.
@article{f1a1c87b09eb403db693264392dd93cd,
title = "Dihydrofolate reductase: a potential drug target in trypanosomes and leishmania",
abstract = "Dihydrofolate reductase has successfully been used as a drug target in the area of anti-cancer, anti-bacterial and anti-malarial chemotherapy. Little has been done to evaluate it as a drug target for treatment of the trypanosomiases and leishmaniasis. A crystal structure of Leishmania major dihydrofolate reductase has been published. In this paper, we describe the modelling of Trypanosoma cruzi and Trypanosoma brucei dihydrofolate reductases based on this crystal structure. These structures and models have been used in the comparison of protozoan, bacterial and human enzymes in order to highlight the different features that can be used in the design of selective anti-protozoan agents. Comparison has been made between residues present in the active site, the accessibility of these residues, charge distribution in the active site, and the shape and size of the active sites. Whilst there is a high degree of similarity between protozoan, human and bacterial dihydrofolate reductase active sites, there are differences that provide potential for selective drug design. In particular, we have identified a set of residues which may be important for selective drug design and identified a larger binding pocket in the protozoan than the human and bacterial enzymes.",
keywords = "Comparative molecular modelling, Dihydrofolate reductase, Drug design, Protein structure",
author = "Fabio Zuccotto and Martin, {Andrew C. R.} and Laskowski, {Roman A.} and Thornton, {Janet M.} and Gilbert, {Ian H.}",
year = "1998",
month = "5",
doi = "10.1023/A:1016085005275",
language = "English",
volume = "12",
pages = "241--257",
journal = "Journal of Computer-Aided Molecular Design",
issn = "0920-654X",
publisher = "Springer Verlag",
number = "3",

}

Dihydrofolate reductase : a potential drug target in trypanosomes and leishmania. / Zuccotto, Fabio; Martin, Andrew C. R. ; Laskowski, Roman A. ; Thornton, Janet M. ; Gilbert, Ian H. .

In: Journal of Computer-Aided Molecular Design, Vol. 12, No. 3, 05.1998, p. 241-257.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dihydrofolate reductase

T2 - a potential drug target in trypanosomes and leishmania

AU - Zuccotto, Fabio

AU - Martin, Andrew C. R.

AU - Laskowski, Roman A.

AU - Thornton, Janet M.

AU - Gilbert, Ian H.

PY - 1998/5

Y1 - 1998/5

N2 - Dihydrofolate reductase has successfully been used as a drug target in the area of anti-cancer, anti-bacterial and anti-malarial chemotherapy. Little has been done to evaluate it as a drug target for treatment of the trypanosomiases and leishmaniasis. A crystal structure of Leishmania major dihydrofolate reductase has been published. In this paper, we describe the modelling of Trypanosoma cruzi and Trypanosoma brucei dihydrofolate reductases based on this crystal structure. These structures and models have been used in the comparison of protozoan, bacterial and human enzymes in order to highlight the different features that can be used in the design of selective anti-protozoan agents. Comparison has been made between residues present in the active site, the accessibility of these residues, charge distribution in the active site, and the shape and size of the active sites. Whilst there is a high degree of similarity between protozoan, human and bacterial dihydrofolate reductase active sites, there are differences that provide potential for selective drug design. In particular, we have identified a set of residues which may be important for selective drug design and identified a larger binding pocket in the protozoan than the human and bacterial enzymes.

AB - Dihydrofolate reductase has successfully been used as a drug target in the area of anti-cancer, anti-bacterial and anti-malarial chemotherapy. Little has been done to evaluate it as a drug target for treatment of the trypanosomiases and leishmaniasis. A crystal structure of Leishmania major dihydrofolate reductase has been published. In this paper, we describe the modelling of Trypanosoma cruzi and Trypanosoma brucei dihydrofolate reductases based on this crystal structure. These structures and models have been used in the comparison of protozoan, bacterial and human enzymes in order to highlight the different features that can be used in the design of selective anti-protozoan agents. Comparison has been made between residues present in the active site, the accessibility of these residues, charge distribution in the active site, and the shape and size of the active sites. Whilst there is a high degree of similarity between protozoan, human and bacterial dihydrofolate reductase active sites, there are differences that provide potential for selective drug design. In particular, we have identified a set of residues which may be important for selective drug design and identified a larger binding pocket in the protozoan than the human and bacterial enzymes.

KW - Comparative molecular modelling

KW - Dihydrofolate reductase

KW - Drug design

KW - Protein structure

UR - http://www.scopus.com/inward/record.url?scp=0032059055&partnerID=8YFLogxK

U2 - 10.1023/A:1016085005275

DO - 10.1023/A:1016085005275

M3 - Article

VL - 12

SP - 241

EP - 257

JO - Journal of Computer-Aided Molecular Design

JF - Journal of Computer-Aided Molecular Design

SN - 0920-654X

IS - 3

ER -