Dihydrofolate reductase inhibitors design

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. 

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... 

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 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... 

However, in view of its apparent success, this work is bound to advance further our understanding of the modes of action and structure-activity relationships of non-classical antimetabolites, and to produce new leads for the rational design of future drugs for chemotherapy. It should be remembered that it was the rational approach , based on the concepts of antimetabolites and of dihydrofolate reductase inhibitors as chemotherapeutic agents, that has... 

The dihydrofolate reductase inhibitor, methotrexate (Fig. 8.47), was developed as an anticancer drug, whose inhibition of formation of folic acid coenzymes would block purine synthesis. In other words, it was designed to induce a folic acid deficiency. Notice in Figs. 8.50 and 8.51 that formation of dTMP, FGAR, and AICAR also causes the oxidation of tetra-hydrofolate to dihydrofolate. The latter must be reduced by dihydrofolate reductase to tet-rahydrofolate before active coenzyme can form again. Thus, not only does methotrexate inhibit the initial formation of the tetrahydro-folate moiety, it blocks regeneration of the coenzyme form. 

Figure 7.16 Dihydrofolate reductase inhibitors methotrexate and Compound 7, (El-Hamamsy, M.H.R.L et al. Structure-based design, synthesis and preliminary evaluation of selective inhibitors of dihydrofolate reductase from Mycobacterium tuberculosis. Bioorg. Med. Chem. 2007, 15, 4552-4576.), neuraminidase inhibitor Relenza (zanamivir), and CCR5 blocker apiaviroc.

P. R. Gerber, A. E, Mark, and W. F. van Gunsteren,/. Comput.-AidedMol. Design, 7,305 (1993). An Approximate but Efficient Method to Calculate Free Energy Trends by Computer Simulation Application to Dihydrofolate Reductase—Inhibitor Complexes. 

L. F. Kuyper, B. Roth, D. P. Baccanari, R. Ferone, C. R. Beddell, j. Champness, D. Stammers, J. Dann, F. Norrington, D. Baker, and P. Goodford,/. Med. Chem., 28,303 (1985). Receptor-Based Design of Dihydrofolate Reductase Inhibitors Comparison of Crystallographically Determined Enzyme Binding with Enzyme Affinity in a Series of Carboxy-Substituted Trimethoprim Analogues. 

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. 

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

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... 

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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