The effect of 5-substitution in the pyrimidine ring of dUMP on the interaction with thymidylate synthase: Molecular modeling and QSAR

2007 ◽  
Vol 15 (6) ◽  
pp. 2346-2358 ◽  
Author(s):  
Adam Jarmuła ◽  
Piotr Cieplak ◽  
Tadeusz M. Krygowski ◽  
Wojciech Rode
Keyword(s):  
Molecular Modeling ◽  
Thymidylate Synthase ◽  
Pyrimidine Ring

scholarly journals Molecular mechanism of thymidylate synthase-catalyzed reaction and interaction of the enzyme with 2- and/or 4-substituted analogues of dUMP and 5-fluoro-dUMP.

1996 ◽  
Vol 43 (1) ◽  
pp. 133-142 ◽  
Author(s):  
W Rode ◽  
A Leś
Keyword(s):  
Reaction Mechanism ◽  
Molecular Modeling ◽  
Thymidylate Synthase ◽  
Pyrimidine Ring ◽  
Inhibition Mechanism ◽  
Inhibitory Potency ◽  
Thymidylate Synthases ◽  
Binding Inhibition ◽  
Molecular Modeling Studies ◽  
Thymidylate Synthase Inhibitors

Thymidylate synthase is a target enzyme in anticancer, antiviral, antifungal and antiprotozoan chemotherapy. With two dUMP analogues, 5-fluoro-dUMP (FdUMP) and 5-(trifluoromethyl)-dUMP (CF3dUMP), strong thymidylate synthase inhibitors and active forms of drugs, the inhibition mechanism is based on the reaction mechanism. Recent comparative studies of new dUMP analogues, containing more than one substituent in the pyrimidine ring, showed that substitution of the pyrimidine ring C(4) = O group in FdUMP by either C(4) = N-OH group (in N4-hydroxy-FdCMP) or C(4) = S group (in 4-thio-FdUMP) preserves high inhibitory potency of the drug but may alter its specificity for thymidylate synthases from various sources, which differ in sensitivity to slow-binding inhibition by FdUMP. Informations suggesting mechanisms responsible for the foregoing have been reviewed, including results of molecular modeling studies suggesting interaction of the pyrimidine C(4) = O group, or its modification, with the N5,10-methylene.(ABSTRACT TRUNCATED)

scholarly journals Functional Analysis of the Mycobacterium tuberculosis FAD-Dependent Thymidylate Synthase, ThyX, Reveals New Amino Acid Residues Contributing to an Extended ThyX Motif

2008 ◽  
Vol 190 (6) ◽  
pp. 2056-2064 ◽  
Author(s):  
Jonathan E. Ulmer ◽  
Yap Boum ◽  
Christopher D. Thouvenel ◽  
Hannu Myllykallio ◽  
Carol Hopkins Sibley
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Thymidylate Synthase ◽  
Three Dimensional ◽  
Pyrimidine Ring ◽  
Dimensional Structure ◽  
Directed Mutagenesis ◽  
Catalytic Residue ◽  
Amino Acid Residues ◽  
Insight Into

ABSTRACT A novel FAD-dependent thymidylate synthase, ThyX, is present in a variety of eubacteria and archaea, including the mycobacteria. A short motif found in all thyX genes, RHRX7-8S, has been identified. The three-dimensional structure of the Mycobacterium tuberculosis ThyX enzyme has been solved. Building upon this information, we used directed mutagenesis to produce 67 mutants of the M. tuberculosis thyX gene. Each enzyme was assayed to determine its ability to complement the defect in thymidine biosynthesis in a ΔthyA strain of Escherichia coli. Enzymes from selected strains were then tested in vitro for their ability to catalyze the oxidation of NADPH and the release of a proton from position 5 of the pyrimidine ring of dUMP. The results defined an extended motif of amino acids essential to enzyme activity in M. tuberculosis (Y44X24 H69X25R95HRX7 S105XRYX90R199 [with the underlined histidine acting as the catalytic residue and the underlined serine as the nucleophile]) and provided insight into the ThyX reaction mechanism. ThyX is found in a variety of bacterial pathogens but is absent in humans, which depend upon an unrelated thymidylate synthase, ThyA. Therefore, ThyX is a potential target for development of antibacterial drugs.

Interaction of thymidylate synthase with pyridoxal 5'-phosphate as studied by UV/visible difference spectroscopy and molecular modeling

Biochemistry ◽  
1993 ◽  
Vol 32 (44) ◽  
pp. 11819-11824 ◽  
Author(s):  
Daniel V. Santi ◽  
Tian Mei Ouyang ◽  
Anthony K. Tan ◽  
Donald H. Gregory ◽  
Thomas Scanlan ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Thymidylate Synthase ◽  
Difference Spectroscopy ◽  
Uv Visible

scholarly journals Design of Thymidine Analogues Targeting Thymidilate Kinase ofMycobacterium tuberculosis

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Luc Calvin Owono Owono ◽  
Melalie Keita ◽  
Eugene Megnassan ◽  
Vladimir Frecer ◽  
Stanislav Miertus
Keyword(s):  
Free Energy ◽  
Molecular Modeling ◽  
Molecular Design ◽  
Structural Information ◽  
3D Qsar ◽  
3D Models ◽  
Pyrimidine Ring ◽  
Qsar Model ◽  
Active Site Residues ◽  
Pharmacophore Generation

We design here new nanomolar antituberculotics, inhibitors ofMycobacterium tuberculosisthymidine monophosphate kinase (TMPKmt), by means of structure-based molecular design. 3D models of TMPKmt-inhibitor complexes have been prepared from the crystal structure of TMPKmtcocrystallized with the natural substrate deoxythymidine monophosphate (dTMP) (1GSI) for a training set of 15 thymidine analogues (TMDs) with known activity to prepare a QSAR model of interaction establishing a correlation between the free energy of complexation and the biological activity. Subsequent validation of the predictability of the model has been performed with a 3D QSAR pharmacophore generation. The structural information derived from the model served to design new subnanomolar thymidine analogues. From molecular modeling investigations, the agreement between free energy of complexation (ΔΔGcom) andKivalues explains 94% of the TMPKmtinhibition (pKi=-0.2924ΔΔGcom+3.234;R2=0.94) by variation of the computedΔΔGcomand 92% for the pharmacophore (PH4) model (pKi=1.0206×pKipred-0.0832,  R2=0.92). The analysis of contributions from active site residues suggested substitution at the 5-position of pyrimidine ring and various groups at the 5′-position of the ribose. The best inhibitor reached a predictedKiof 0.155 nM. The computational approach through the combined use of molecular modeling and PH4 pharmacophore is helpful in targeted drug design, providing valuable information for the synthesis and prediction of activity of novel antituberculotic agents.

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