High-resolution structures ofTrypanosoma bruceipteridine reductase ligand complexes inform on the placement of new molecular entities in the active site of a potential drug target

Dawson, Alice; Tulloch, L.B.; Barrack, K.L.; Hunter, William N.

doi:10.1107/s0907444910040886

Cited by 24 publications

(41 citation statements)

References 35 publications

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“…The systems chosen comprised seven S⋅⋅⋅O and four Se⋅⋅⋅O interaction motifs (Table ; Figure ). In the S‐containing ligands selected, the S atom was present in rings – mostly aromatic, monocyclic (3FUN, 3SUR, 4HYI, 5HMI, 5EJ9) or bicyclic (3MCV, 3VQS,). All of these S‐containing ligand model systems had an S⋅⋅⋅O contact with protein oxygen atoms coming from the backbone carbonyl, Asn side‐chain amide or Tyr/Ser hydroxyl (Table S1; Figure ).…”

Section: Resultsmentioning

confidence: 99%

Chalcogen Bonding in Protein−Ligand Complexes: PDB Survey and Quantum Mechanical Calculations

2018

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A chalcogen bond is a nonclassical noncovalent interaction which can stabilise small-molecule crystals as well as protein structures. Here, we systematically explore the stabilising potential of chalcogen bonding in protein-ligand complexes in the Protein Data Bank (PDB). We have found that a large fraction (23 %) of complexes with a S/Se-containing ligand feature close S/Se⋅⋅⋅O/N/S contacts. Eleven non-redundant representative potential S/Se⋅⋅⋅O chalcogen-bond motifs were selected and truncated to model systems and seven more model systems were prepared by S-to-Se substitution. These systems were then subjected to analysis by quantum chemical (QM) methods-electrostatic potential, geometry optimisation or interaction energy calculations, including solvent effects. The QM calculations indicate that chalcogen bonding does indeed play a dominant role in stabilising some of the interaction motifs studied. We thus advocate further exploration of chalcogen bonding with the aim of potential future use in structure-based drug design.

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Section: Resultsmentioning

confidence: 99%

Chalcogen Bonding in Protein−Ligand Complexes: PDB Survey and Quantum Mechanical Calculations

2018

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“…Multiple sequence alignment (MSA) of the TbPTR1, TcPTR1, LmPTR1 and HsDHRS4 orthologue protein sequences showed conservation of several key residues within the SDR family signature (residues ASP161-ALA193) as well as in the substrate binding loop (residues SER207-GLU215) present in trypanosomatids (Figure2B). Pterin and folate substrates along with inhibitors interact with PTR1 complexes quite similarly, often via binding in a π-sandwich between the NADPH nicotinamide ring and residue PHE97 [19,26]. The NADPH cofactor is known to be essential in creating both the substrate binding site as well as the catalytic center [19,27].…”

Section: Overview Of Ptr1 Structure and Conservationmentioning

confidence: 99%

“…The NADPH cofactor is known to be essential in creating both the substrate binding site as well as the catalytic center [19,27]. ARG14, SER95, PHE97, ASP161, and TYR174 are important residues that interact with the folate and pterin substrates, and are well conserved among the trypanosomatids [19,26] ( Figure 2B). The structural superimposition of TbPTR1 (PDB:2X9N) [26] with T. cruzi PTR2 (PDB:1MXH) [28], LmPTR1(PDB:1E92) [16], and H. sapiens DHRS4 (PDB: 304R) gave RMS values of 0.4, 0.5, and 1.6, indicating that the trypanosomatid PTR1s are structurally very similar.…”

Section: Overview Of Ptr1 Structure and Conservationmentioning

confidence: 99%

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Identification of Novel Inhibitors of Pteridine Reductase 1 in Trypanosoma brucei via Computational Structure-Based Approaches and In Vitro Inhibition Assays

Kimuda¹,

Laming²,

Hoppe³

et al. 2018

Preprint

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Pteridine reductase 1 is a trypanosomatid multifunctional enzyme that provides a mechanism for escape of Dihydrofolate reductase (DHFR) inhibition. This is because PTR1 can reduce pterins and folates. Trypanosomes require folates and pterins for survival and are unable to synthesize them de novo. Currently there are no anti-folate based Human African Trypanosomiasis (HAT) chemotherapeutics in use. Thus, successful dual inhibition of TbDHFR and TbPTR1 has implications in the exploitation of anti-folates. We carried out molecular docking of a ligand library of 5742 compounds against TbPTR1 and identified 18 compounds showing promising binding modes. The protein-ligand complexes were subjected to Molecular dynamics to characterize their molecular interactions and energetics followed by in vitro testing. In this study, we identified five potential TbPTR1 inhibitors that showed low micromolar Trypanosome growth inhibition in in vitro experiments with no significant human cell cytotoxicity. Compounds RUBi004, RUBi007, RUBi014, and RUBi018 displayed moderate to strong antagonism when used in combination with the known TbDHFR inhibitor, WR99210. This gave an indication that the compounds might inhibit both TbPTR1 and TbDHFR. RUBi016 showed an additive effect in the isobologram assay. Our results provide a basis for scaffold optimization for further studies in the development of HAT antifolates.

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“…Plasmepsin II (PMII) 1SME [224]; 1LEE, 1LF2 [225]; 1LF3, 1LF4 [226]; 2BJU [227]; 2IGX, 2IGY [228]; 3F9Q [229]; 1M43 [230]; 1ME6 [231]; 1W6H, 1W6I [232]; 1XDH, 1XE5, 1XE6 [233] Plasmepsin IV (PMIV) 1LS5 [225] Proline racemase (PRACA) 1W61, 1W62 [234] Protein Kinase 5 (PK5) 1OB3, 1V0O, 1V0P [235] Protein tyrosine phosphatase 1 (PTP1) 3M4U [236] 4AZ1 [237] Pteridine reductase 1 (PTR1) 2XOX [238] 1E7W, 1E92 [239]; 1W0C [240]; 2BF7, 2BFA,2BFM, 2BFO, 2BFP [241]; 2QHX, 3H4V [242] 2C7V [243]; 2WD7, 2WD8, 3GN1, 3GN2 [244]; 2VZ0 [245]; 3BMC, 3BMN, 3BMO, 3BMQ, 3JQ6, 3JQ7, 3JQ8, 3JQ9, 3JQA, 3JQB, 3JQC, 3JQD, 3JQE, 3JQF, 3JQG [246]; 2X9N, 2X9G, 2X9V, 3MCV [247]; 2YHI [248] Pteridine reductase 2 (PTR2) 1MXF, 1MXH [249] Purine nucleoside phosphorylase (PNP) 1NW4, 1Q1G [250]; 2BSX, 1SQ6 [251]; 3ENZ [252] Pyridoxal kinase (PdxK) 3ZS7 [253] Pyruvate kinase (PYK)…”

Section: Brucei T Cruzimentioning

confidence: 99%

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

Ogungbe

Setzer

2016

Molecules

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Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a constant need to discover new chemotherapeutic agents for these parasitic infections, and natural products continue to serve as a potential source. This review presents molecular docking studies of potential phytochemicals that target key protein targets in Leishmania spp., Trypanosoma spp., and Plasmodium spp.

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High-resolution structures ofTrypanosoma bruceipteridine reductase ligand complexes inform on the placement of new molecular entities in the active site of a potential drug target

Cited by 24 publications

References 35 publications

Chalcogen Bonding in Protein−Ligand Complexes: PDB Survey and Quantum Mechanical Calculations

Chalcogen Bonding in Protein−Ligand Complexes: PDB Survey and Quantum Mechanical Calculations

Identification of Novel Inhibitors of Pteridine Reductase 1 in <em>Trypanosoma brucei</em> via Computational Structure-Based Approaches and <em>In Vitro</em> Inhibition Assays

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

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