Structures of native human thymidine phosphorylase and in complex with 5-iodouracil

Mitsiki, E; Papageorgiou, Anastassios C.; Iyer, Shalini; Thiyagarajan, N.; Prior, Stephen H.; Sleep, Darrell; Finnis, C; Acharya, K. Ravi

doi:10.1016/j.bbrc.2009.06.104

Cited by 40 publications

(46 citation statements)

References 22 publications

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“…By performing docking on various analogues of the 5‐FU as well as the MD simulations, both repetition runs and the extra‐long MD simulations of up to 500 ns, no other binding site with potential for accommodating 5‐FU, better than that of the known active site, was observed. This supports, and is in agreement with, the available experimental data (Mitsiki et al, ).…”

Section: Discussionsupporting

confidence: 93%

“…The amino acid sequence of hTP (2WK6; Mitsiki et al, ) was compared to BsPyNP (1BRW; Pugmire & Ealick, ) and EcTP (1AZY; Pugmire, Cook, Jasanoff, Walter, & Ealick, ) using Clustal Omega tool (Kelley & Sternberg, ) which showed EcTP and BsPYNP share approximately 40%–50% sequence‐similarities to hTP. The residues 1–32 of the N‐terminus of hTP were not present in BsPyNP or EcTP, and also, their secondary structure was not solved in 2WK6.pdb (Mitsiki et al, ; Figure S2).…”

Section: Resultsmentioning

confidence: 99%

“…The glycine loop (residues 144–154) is 100% conserved among the three proteins. His116, Arg202, Ser217, and Lys221 of the loop are involved in hydrogen bonding with 5‐IU according to the crystal structure (Mitsiki et al, ). Similar interactions were reported in the crystal structure of the hTP complex with uracil derivative, 4‐chloro‐6‐(1‐(2‐iminopyrrolidinyl) methyl uracil (CMU; Norman et al, ), as well as in hTP and thymine (2J0F; El Omari et al, ), or in BsPyNP and uracil complex (1BRW; Pugmire & Ealick, ).…”

Section: Resultsmentioning

confidence: 99%

“…The DPD structure (1H7X) was solved with a resolution of 2.0 Å from recombinant pig liver, which shares a high amino acid sequence identity with human DPD with nearly 93% sequence identity (Dobritzsch et al, 2001). FlexX commercial docking software (Gohlke, Hendlich, & Klebe, 2000;Rarey, Kramer, & Lengauer, 1999;Rarey, Kramer, Lengauer, & Klebe, 1996) embedded in LeadIT software package (version 2.1.8) was used to dock 5-FU (protonated and unprotonated) and its analogues into the binding site of hTP and DPD in separate experiments, to search for the most energetically favorable binding conformations of each ligand with hTP (Mitsiki et al, 2009).…”

Section: Preparation Of the Starting Structuresmentioning

confidence: 99%

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Interdomain twists of human thymidine phosphorylase and its active–inactive conformations: Binding of 5‐FU and its analogues to human thymidine phosphorylase versus dihydropyrimidine dehydrogenase

et al. 2019

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5‐fluorouracil (5‐FU) is an anticancer drug, which inhibits human thymidine phosphorylase (hTP) and plays a key role in maintaining the process of DNA replication and repair. It is involved in regulating pyrimidine nucleotide production, by which it inhibits the mechanism of cell proliferation and cancerous tumor growth. However, up to 80% of the administered drug is metabolized by dihydropyrimidine dehydrogenase (DPD). This work compares binding of 5‐FU and its analogues to hTP and DPD, and suggests strategies to reduce drug binding to DPD to decrease the required dose of 5‐FU. An important feature between the proteins studied here was the difference of charge distribution in their binding sites, which can be exploited for designing drugs to selectively bind to the hTP. The 5‐FU presence was thought to be required for a closed conformation. Comparison of the calculation results pertaining to unliganded and liganded protein showed that hTP could still undergo open–closed conformations in the absence of the ligand; however, the presence of a positively charged ligand better stabilizes the closed conformation and rigidifies the core region of the protein more than unliganded or neutral liganded system. The study has also shown that one of the three hinge segments linking the two major α and α/β domains of the hTP is an important contributing factor to the enzyme's open–close conformational twist during its inactivation–activation process. In addition, the angle between the α/β‐domain and the α‐domain has shown to undergo wide rotations over the course of MD simulation in the absence of a phosphate, suggesting that it contributes to the stabilization of the closed conformation of the hTP.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Preparation Of the Starting Structuresmentioning

confidence: 99%

See 2 more Smart Citations

Interdomain twists of human thymidine phosphorylase and its active–inactive conformations: Binding of 5‐FU and its analogues to human thymidine phosphorylase versus dihydropyrimidine dehydrogenase

et al. 2019

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“…To explore the plausible binding mode and molecular interactions responsible for enzyme inhibition of the synthesized compounds, geometry‐optimized structure of compounds was allowed to dock at the active site of TP (PDB code: 2WK6) using SYBYL‐X 1.3. The lowest energy conformation of the compounds was adopted to analyze the docking results.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro Evaluation of 1,2,4‐Triazolo[1,5‐a][1,3,5]triazine Derivatives as Thymidine Phosphorylase Inhibitors

et al. 2013

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In our lead finding program, a series of 1,2,4-triazolo[1,5-a][1,3,5]triazine derivatives were synthesized, and their in vitro thymidine phosphorylase inhibitory potential was explored. Among the different derivatives, compounds having keto group (C = O) at C7 and thioketo group (C = S) at C5 positions showed varying degrees of TP inhibitory activity comparable with positive control, 7-deazaxanthine (7-DX, 2) (IC50 value = 42.63 μm). Enzyme inhibition kinetics study suggested that compound IVn behaved as a mixed-type inhibitor of the enzyme with respect to thymidine (dThd) as a variable substrate. Compound IVn was also found to inhibit PMA-induced MMP-9 expression in MDA-MB-231 cells at sublethal concentrations. Computational docking study was performed to illustrate the enzyme inhibition kinetics and to explore the ligand-enzyme interactions.

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Design, Synthesis, in Vitro, and in Silico Evaluations of 1,3,4‐Oxadiazole Derivatives Linked to the Pyrrolo[2,3‐d]pyrimidine Moieties as Potent Antimicrobial Targets

Lal Patel,

Kumar Sureddy,

Boddupalli

et al. 2024

ChemistrySelect

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Abstract1,3,4‐Oxadiazole and its derivatives are well known assorted motif in drug design and development. The development of bacterial infection drug resistance serves as justification for the discovery of novel antimicrobial drugs. Thus, a novel series of 1,3,4‐oxadiazole derivatives linked to pyrrolo[2,3‐d]pyrimidine 6 a–f and 7 a–e was designed, synthesized and fully characterized by 1H‐NMR, 13C‐NMR, FT‐IR and mass spectroscopic analysis. All of the compounds′ in‐vitro antibacterial and antifungal activities were reported, and final oxadiazoles 6 d, 6 e, 6 f, and 7 e showed excellent antimicrobial inhibitory activity as compared to standard drugs. The compounds 6 f and 7 a exhibited potent antifungal activity as a potent inhibitor against C. albicans with MICs 4.0±0.03, 7.5±0.02 μg/mL respectively. In order to determine the different binding interactions that the most active oxadiazoles had with the Staphylococcus aureus DHFR enzyme, a docking study was conducted. The results indicated that the residues of amino acid Thr96(X), Leu62(X), Arg44(X), Asn18(X), Glu17(X), Lys45(X), Thr121(X), Gln95(X), Asp120(X), Ser64(X), Gly94(X), and Phe16(X) had promising energy value, within the range of −6.84 to −9.63 kcal/mol (PDB: 3FRA). The most effective inhibitors, 6 and 7, also underwent in silico ADMET tests to predict their pharmacokinetic and physicochemical characteristics.

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Structures of native human thymidine phosphorylase and in complex with 5-iodouracil

Cited by 40 publications

References 22 publications

Interdomain twists of human thymidine phosphorylase and its active–inactive conformations: Binding of 5‐FU and its analogues to human thymidine phosphorylase versus dihydropyrimidine dehydrogenase

Interdomain twists of human thymidine phosphorylase and its active–inactive conformations: Binding of 5‐FU and its analogues to human thymidine phosphorylase versus dihydropyrimidine dehydrogenase

Synthesis and in vitro Evaluation of 1,2,4‐Triazolo[1,5‐a][1,3,5]triazine Derivatives as Thymidine Phosphorylase Inhibitors

Design, Synthesis, in Vitro, and in Silico Evaluations of 1,3,4‐Oxadiazole Derivatives Linked to the Pyrrolo[2,3‐d]pyrimidine Moieties as Potent Antimicrobial Targets

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