Dihydrofolate reductase design

T A and H Kalayeh 1991. Applications of Neural Networks in Quantitative Structure-Activity ationships of Dihydrofolate Reductase Inhibitors, journal of Medicinal Chemistry 34 2824-2836. ik M and R C Glen 1992. Applications of Rule-induction in the Derivation of Quantitative icture-Activity Relationships. Journal of Computer-Aided Molecular Design 6 349-383. 

Kuyper LF, Roth B, Baccanari DP, Ferone R, Beddell CR, Champness JN et al. Receptor-based design of dihydrofolate reductase inhibitors comparison of crys-tallographically determined enzyme binding with enzyme affinity in a series of carboxy-substituted trimethoprim analogues. J Med Chem 1982 25 1120-2... 

Gschwend DA, Sirawaraporn W, Santi DV, Kuntz ID. Specificity in structure-based drug design identification of a novel, selective inhibitor of Pneumocystis carinii dihydrofolate reductase. Proteins Struct Funct Genet 1997 29 59-67. 

Wyss PC, Gerber P, Hartman PG, Hubschwerlen C, Locher H, Marty HP, Stahl M. Novel dihydrofolate reductase inhibitors. Structure-based versus diversity-based library design and high-throughput synthesis and screening. J Med Chem 2003 46 2304-12. 

Dihydrofolate Reductase Free Energy Calculations for the Design of Mechanism-Based Inhibitors... 

J. E. Gready, Design of new mechanism-based substrates for dihydrofolate reductase, in ... 

Studies using free energy calculations for the design and analysis of potential drug candidates are reviewed in section five. The chapters in this section cover drug discovery programs targeting fructose 1,6-bisphosphatase (diabetes), COX-2 (inflammation), SRC SH2 domain (osteoporosis and cancer), HIV reverse transcriptase (AIDS), HIV-1 protease (AIDS), thymidylate synthase (cancer), dihydrofolate reductase (cancer) and adenosine deaminase (immunosuppression, myocardial ischemia). 

Dihydrofolate reductase inhibitors from structure-based library design... 

The discovery of novel dihydrofolate reductase inhibitors by structure-based library design based on a 5-(dialkylamino)-2,4-diaminopyrimidine scaffold was reported by Wyss et al. [279] (cf Figure 4.5g). On the basis of a diaminopyrimidine core, a virtual... 

Zimmermann, M., Tresch, A., Maass, A., Hofmann, M. Drilling into a HTS data set of E. coli dihydrofolate reductase. In Proceedings of the 15th European Symposium on Quantative Structure-Activity Relationships 2004, Aki E., Yalcin J. (eds) published by Computer Aided Drug Design Development Society, Turkey,... 

Gangjee, A. Guo, X. Queener, S. F. Cody, V. Galitsky, N. Luft, J. R. Pangborn, W. Selective pneumocystis carinii dihydrofolate reductase inhibitors design, synthesis, and biological evaluation of new 2,4-diamino-5-substituted-furo[2,3-d]pyrimidines./. Med. Chem. 1998, 42, 1263-1271. 

The active-site-directed inhibition of enzymes has been an important research topic in pharmaceutical drug design (Sandler, 1980). An early development of anti-cancer agents involved inhibitions of dihydrofolate reductase and thymidylate synthetase. Search enzyme resource sites for kinetic data (turnover number, Km and Kt) of these two enzymes. 

In silico structure-based design of a novel class of potent and selective small peptide inhibitor of Mycobacterium tuberculosis Dihydrofolate reductase, a potential target for anti-TB drug discovery. Mol Divers 14(3) 595-604... 

Pelletier, J. N., Campbell-Valois, F. X., and Michnick, S. W. (1998). Oligomerization domain-directed reassembly of active dihydrofolate reductase from rationally designed fragments. Proc. Natl. Acad. Sci. USA, 95, 12141-12146. 

More recently Michnick and co-workers have introduced a dihydrofolate reductase complementation system, which seems to be particularly robust [61 - 65], They attribute the success of this system to the fact that the N-terminal (1 - 105) and C-terminal (106 - 186) DHFR fragments do not fold until they are dimerized. In addition to the obvious selection for essential metabolites dependent on the reduction of dihydrofolate to tetrahydrofolate, protein-protein interactions are detected based on the retention of a fluorescein-methotrexate conjugate. Several other enzymes have been employed for the design of complementation assays, including green fluorescent protein, which allows screens based on fluorescence or FRET [66 - 68]. As with the bacterial transcription assays, these complementation systems are new. It will be interesting to see if, as the selections are optimized, these systems prove competitive with the Y2H assay. 

Genet., 29, 59 (1997). Specificity in Structure-Based Drug Design Identification of a Novel, Selective Inhibitor of Pneumocystis carinii Dihydrofolate Reductase. 

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