Three-dimensional structure of M. tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs.

@article{Li2000ThreedimensionalSO,
  title={Three-dimensional structure of M. tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs.},
  author={R. Li and Rachada Sirawaraporn and Penchit Chitnumsub and Worachart Sirawaraporn and Jason M. Wooden and F K Athappilly and Stewart Turley and Wim G. J. Hol},
  journal={Journal of molecular biology},
  year={2000},
  volume={295 2},
  pages={
          307-23
        }
}
Dihydrofolate reductase (DHFR) catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate and is essential for the synthesis of thymidylate, purines and several amino acids. Inhibition of the enzyme's activity leads to arrest of DNA synthesis and cell death. The enzyme has been studied extensively as a drug target for bacterial, protozoal and fungal infections, and also for neoplastic and autoimmune diseases. Here, we report the crystal structure of dihydrofolate reductase… Expand
Structure-based design, synthesis and preliminary evaluation of selective inhibitors of dihydrofolate reductase from Mycobacterium tuberculosis.
TLDR
Preliminary assay of the abilities of these compounds to inhibit the growth of TB5 Saccharomyces cerevisiae carrying the DHFR genes from M. tuberculosis, human and yeast indicated that 5-phenyl-6-((3R,4S)-3,4,5-trihydroxypentyl)pyrimidine-2,4-diamine selectively inhibited M.culosis DHFR and had little effect on the human or yeast enzymes. Expand
Mycobacterium tuberculosis dihydrofolate reductase reveals two conformational states and a possible low affinity mechanism to antifolate drugs.
TLDR
A structural, site-directed mutagenesis and calorimetric analysis of Mycobacterium tuberculosis DHFR in complex with classical DHFR inhibitors provides insights into the weak inhibition of MtDHFR by trimethoprim and other antifolate drugs, such as pyrimethamine and cycloguanil. Expand
Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates.
TLDR
The structural comparisons and analysis described in this work provide new information about the plasticity of MtDHFR and the binding effects of different antifolates, as well as the affinities of diaverdine and methotrexate. Expand
Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates
Tuberculosis is a disease caused by Mycobacterium tuberculosis and is the leading cause of death from a single infectious pathogen, with a high prevalence in developing countries in Africa and Asia.Expand
Development of Selective Inhibitors of Dihydrofolate Reductase (DHFR) of Mycobacterium Tuberculosis
TLDR
This project focuses on the development of new inhibitors with improved potency and selectivity for the M. tuberculosis enzyme, inhibitors containing a 5-phenyl group were targeted in order to increase lipophilicity and binding to the enzyme, whilst reducing binding toThe human enzyme. Expand
Structural characteristics of antifolate dihydrofolate reductase enzyme interactions
The ubiquitous enzyme dihydrofolate reductase (DHFR) is responsible for the reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate in an NADPH-dependent manner. It is also a key pharmacologicalExpand
Structural and Dynamics Perspectives on the Binding of Substrate and Inhibitors in Mycobacterium tuberculosis DHFR
TLDR
The key factors that promote the binding of P157 and P169 on M. tuberculosis DHFR (mtbDHFR) reveal opportunities for using these compounds as novel anti-tuberculosis drugs. Expand
Using a fragment-based approach to identify alternative chemical scaffolds targeting dihydrofolate reductase from Mycobacterium tuberculosis.
TLDR
An integrated fragment-based drug discovery approach to target MtDHFR that has identified hits with scaffolds not yet explored in any previous drug design campaign for this enzyme is described. Expand
Using a fragment-based approach to identify novel chemical scaffolds targeting the dihydrofolate reductase (DHFR) from Mycobacterium tuberculosis
TLDR
An integrated fragment-based drug discovery approach to target MtDHFR that has identified hits with scaffolds not yet explored in any previous drug design campaign for this enzyme is described. Expand
Structures of Leishmania major pteridine reductase complexes reveal the active site features important for ligand binding and to guide inhibitor design.
TLDR
Ternary complexes with cofactor and CB3717 and trimethoprim, potent inhibitors of thymidylate synthase and dihydrofolate reductase, respectively, have been characterized and molecular detail provided by these complex structures identifies the important interactions necessary to assist the structure-based development of novel enzyme inhibitors of potential therapeutic value. Expand
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References

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TLDR
A set of residues which may be important for selective drug design are identified and a larger binding pocket in the protozoan is identified than the human and bacterial enzymes. Expand
High-affinity inhibitors of dihydrofolate reductase: antimicrobial and anticancer activities of 7,8-dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with small molecular size.
TLDR
A series of 7,8-dialkylpyrrolo[3,2-f]quinazolines prepared as inhibitors of dihydrofolate reductase (DHFR) were designed to be relatively small and compact, and showed significant distribution into lung and brain tissue. Expand
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Progress has been made recently in understanding the biochemical basis for the selectivity of this drug and the biochemical mechanism (or mechanisms) responsible for the development of resistance to treatment with the drug, which has led to a new generation of DHFR inhibitors that are now in clinical trials. Expand
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TLDR
It is demonstrated that lipophilic antifolates can be synthesized which are more active against mycobacteria than trimethoprim and which possess selective toxicity. Expand
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TLDR
It is proposed that this 1-A overlap of the binding sites for folate's pteridine ring and the dihydronicotinamide ring of NADPH accelerates the reduction of both folate and 7,8-dihydrofolate by simultaneously binding substrate and cofactor with a sub van der Waals separation that is optimal for hydride transfer. Expand
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TLDR
It is confirmed that malarial DHFRs offer potential binding interactions in the folate-binding pocket distinct from those exploited by pyrimethamine and cycloguanil. Expand
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TLDR
Refinement has led to a revised description of the details of methotrexate binding, and a hypothetical model for substrate binding is proposed in which the pteridine ring is turned upside down while all protein and solvent atoms remain fixed. Expand
Comparison of two independent crystal structures of human dihydrofolate reductase ternary complexes reduced with nicotinamide adenine dinucleotide phosphate and the very tight-binding inhibitor PT523.
Structural data for two independent crystal forms (monoclinic, C2, and orthorhombic, P2(1)2(1)2(1)) of the ternary complex of the potent antitumor agent PT523 [N alpha-(4-amino-4-deoxypteroyl)-NExpand
Transformation with human dihydrofolate reductase renders malaria parasites insensitive to WR99210 but does not affect the intrinsic activity of proguanil.
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TLDR
It is demonstrated that the only significant action of WR99210 is against parasite DHFR, and the transformation system described here has the advantage that P. falciparum drug-resistant lines are uniformly sensitive to methotrexate, which provides an approach for screening and identifying novel DHFR inhibitors that will be important in combined chemotherapeutic formulations against malaria. Expand
Loop and subdomain movements in the mechanism of Escherichia coli dihydrofolate reductase: crystallographic evidence.
TLDR
Loop movement, not observed in vertebrate DHFR structures, appears to similarly adjust the pABG cleft width, suggesting that these movements are important for catalysis, and may explain how THF release is assisted by NADPH binding. Expand
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