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Phosphonic Acids And Phosphonates As Antimetabolites
Published in Richard L. Hilderbrand, The Role of Phosphonates in Living Systems, 2018
This material competes with dTMP as a substrate for the thymidylate kinase and in certain systems is transported and exhibits cytotoxicity. Lazarus et al.243 found that the ATP analogue (Structure 86) is a competitive inhibitor of ATP with hexokinase and 3-phosphoglycerate kinase and of the utilization of ATP by phosphofructokinase.
Zidovudine
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Catherine L. Cherry, Suzanne M. Crowe
Phosphorylation of zidovudine by cellular thymidine kinase (TK) to the monophosphate derivative occurs in both uninfected and HIV-infected cells and is as efficient as phosphorylation of thymidine, the native substrate of TK (Km values for zidovudine and thymidine are 3.0 and 2.9 μM, respectively) (Furman et al., 1986). Subsequent phosphorylation to the diphosphate derivative catalyzed by cellular thymidylate kinase is less efficient and a rate-limiting step in zidovudine activation (Kakuda, 2000). Because of poor substrate specificity of zidovudine monophosphate for thymidylate kinase, zidovudine monophosphate accounts for more than 95% of intracellular zidovudine (Furman et al., 1986; Agarwal and Mian, 1991). The final conversion of zidovudine diphosphate to zidovudine triphosphate is by cellular nucleoside diphosphate kinase (Bourdais et al., 1996), a step in zidovudine activation that may also be rate limiting (Kakuda, 2000).
1-(Piperidin-3-yl)thymine amides as inhibitors of M. tuberculosis thymidylate kinase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Yanlin Jian, Martijn D. P. Risseeuw, Mathy Froeyen, Lijun Song, Davie Cappoen, Paul Cos, Hélène Munier-Lehmann, Serge van Calenbergh
Using the Gram-positive bacterial thymidylate kinase inhibitor 1 (Figure 2) disclosed by Astra Zeneca7 as a starting point, our research group is trying to identify potent non-nucleoside MtbTMPK inhibitors25. These efforts resulted in the identification of the regiomeric racemates 2 and 3, of which the latter showed the best MtbTMPK inhibitory activity and was therefore selected for further optimisation. In this study, we synthesised a series of D-ring substituted analogues of 3 and evaluated these as MtbTMPK inhibitors (Figure 2).
Thais savignyi tissue extract: bioactivity, chemical composition, and molecular docking
Published in Pharmaceutical Biology, 2022
Mohamed R. Habib, Ahmed A. Hamed, Rasha E. M. Ali, Khaled M. Zayed, Rasha M. Gad El-Karim, Rehab Sabour, Hanaa M. Abu El-Einin, Mosad A. Ghareeb
Thymidylate kinase (TMK) is considered the key enzyme in the production of thymidine triphosphate and acts by catalysing the conversion of thymidine monophosphate into thymidine diphosphate (dTDP), which is subsequently phosphorylated by nucleoside diphosphate kinase to produce thymidine triphosphate (Hu et al. 2005; Cui et al. 2013). The thymidylate kinase enzyme plays a critical role in bacterial DNA biosynthesis. Therefore, TMK is a promising target for antibacterial drugs (Kawatkar et al. 2014). Indeed, TMK was validated as a potent antibacterial target for drugs designed to treat gram-positive bacterial infections (Keating et al. 2012). Docking studies using the MOE program (Barakat et al. 2018; Mustafa and Mostafa 2020) were carried out to predict the most suitable binding pose of identified compounds (1–7) in Ts-EtOAc extract using the bacterial enzyme; thymidylate kinase (PDB: 4QGG). The potencies of these identified compounds were evaluated computationally based on their docking scores (energy scores). This score represents the strength of the non-covalent interactions among numerous molecules within the binding pocket of a target protein. The higher the negative score is, the more beneficial interactions between the chemical and the target protein are. Most of the investigated compounds showed considerable binding interactions with important residues in the active site TMK (ID: 4QGG). However, compound 4 (2-[1-(4-cyano-1,2,3,4-tetrahydronaphthyl)] propanenitrile) showed the highest negative score of −9.117 kcal/mol based on performing binding interactions inside the active binding site via the formation of four hydrogen bonds with Arg36, Arg48, Arg92, and Gln37. Moreover, targeting the same bacterial enzyme, Barakat et al. (2018) found docking score of a synthetic pyrazole-dimedone derivative to be −6.86 kcal/mol through binding interactions with the amino groups of Arg70 and Gln101 and the crucial residues Phe66 and Arg92 of TMK. Moreover, Saminathan et al. (2020) docked two pyrazoline-thiocyanatoethanone derivatives; 1-(5-[4-fluorophenyl]-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-thiocyanatoethanone (FSCN) and 1-(5-[4-chlorophenyl]-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-thiocyanatoethanone (ClSCN) against the thymidylate kinase (ID: 4QGG). Their results showed that the two compounds formed different bonded interactions between compounds and TMK binding site residues with binding energies of −7.8 and −7.3 kJ/mol, respectively, for FSCN and ClSCN. The interactions of the FSCN involved six hydrogen bonds with the Arg36, Arg48, Arg92, and Thr16 residues of TMK, while the compound ClSCN interacted with protein 4QGG through five hydrogen bonds with the residues Arg36, Arg92, and Thr16 (Saminathan et al. 2020).