Dihydrofolate reductase inhibitors applications

Gerber, P. R., Mark, A. E., van Gunsteren, W. F. An approximate but efficient method to calculate free energy trends by computer simulation Application to dihydrofolate reductase-inhibitor complexes. J. Comp. Aid. Mol. Desgn 7 (1993) 305-323... 

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. 

TA Andrea, H Kalayeh. Applications of neural networks in quantitative structure-activity relationships of dihydrofolate reductase inhibitors. J Med Chem 34 2824-2836, 1991. 

The sulfas, including co-trimoxazole (sulfamethoxazole plus trimethoprim, see p. 293), are bacteriostatic. These drugs are active against selected enterobacteria, chlamydia, Pneumocystis, and nocardia. Typical clinical applications are shown in Figure 29.3. In addition, sulfadiazine [sul fa DYE a zeen] in combination with the dihydrofolate reductase inhibitor pyrimethamine [py ri METH a meen] is the only effective form of chemotherapy for toxoplasmosis (p. 353). 

Hopfinger, A.J. (1983). Theory and Application of Molecular Potential Energy Fields in Molecular Shape Analysis A Quantitative Structure-Activity Relationship Study of 2,4-Diamino-5-benzylpyrimidines as Dihydrofolate Reductase Inhibitors. J.Med.Chem.,26, 990-996. 

Hopfinger, A.J. (1983) Theory and application of molecular potential energy fields in molecular shape analysis a quantitative structure-activity relationship study of 2,4-diamino-5-benzylpyrimidines as dihydrofolate reductase inhibitors. J. Med. Chem., 26,... 

Polanski, J., Bak, A., Gieledak, R. and Magdziarz, T. (2004) Self-organizing neural networks for modeling robust 3D and 4D QSAR application to dihydrofolate reductase inhibitors. Molecules, 9, 1148-1159. 

Andrea, T. A. Kalayeh, H. (1991). Applications of neural networks in quantitative structure-activity relationships of dihydrofolate reductase inhibitors. Journal of Medicinal Chemistry. Vol. 34, pp. 2824-2836. ISSN 0022-2623 Aparido, R. Aparicio-Ruiz, R. (2002). Chemometrics as an aid in authentication. In Oils and Fats Authentication, M Jee (Ed.), 156-180, Blackwell Publishing and CRC Press, ISBN 1841273309, Oxford, UK and FL, USA Bishop, CM. (2000). Neural Networks for Pattern Recognition, Oxford University Press, ISBN 0198538642, NY, USA... 

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. 

An Approximate But Efficient Method to Calculate Free Energy Trends by Computer Simulation Application to Dihydrofolate Reductase-Inhibitor Complexes. 

A review is given of the application of Molecular Dynamics (MD) computer simulation to complex molecular systems. Three topics are treated in particular the computation of free energy from simulations, applied to the prediction of the binding constant of an inhibitor to the enzyme dihydrofolate reductase the use of MD simulations in structural refinements based on two-dimensional high-resolution nuclear magnetic resonance data, applied to the lac repressor headpiece the simulation of a hydrated lipid bilayer in atomic detail. The latter shows a rather diffuse structure of the hydrophilic head group layer with considerable local compensation of charge density. 

The second equation is often applicable to equilibrium situations such as those found in vitro. Sometimes, different dependencies on tt are found for substituents in different parts of the molecule. The hydrolysis rates of substituted phenyl / -D-glucosides by emulsin, for instance, have been shown by Hansch (I) to depend on w for the para substituents but not on tt for the meta substituents. Some of Baker s results (2) on the 5,6-disubstituted-2,4-diaminopyrimidines as inhibitors of dihydrofolate reductase can be correlated with tt only by choosing tt for the most lipophilic of the two substituents (3). Only a part of the molecule need be desolvated on combining with the receptor. 

NATA, N-L-acetyltryptophanamide BSND, benzenesulfonamide BSFN, benzenesulfonate Sta, statine BZD, benzamidine CFM, coformycin MTX, methotrexate TMP, trimethoprim PT, pterin NPT, N5-deazapterin THP, tetrahydropyrrole Bz, benzene ADA, adenosine deaminase HCAIl, human carbonic anhydrase II TS, thymidyiate synifaase DHFR, dihydrofolate reductase MBP, mannose bindnig protein HEI, hydroxyethylene inhibitor HPR, (6R)-6-hydroxy-l,6 dihydropurine riboside (R),R configuration (S),S configuration NA, not available or not applicable. 

L. F. Kuyper, in Computer-Assisted Drug Design Methods and Applications. T. J. Perun and C. L. Probst, Eds., Dekker, New York, 1989, pp. 327-369. Inhibitors of Dihydrofolate Reductase. (See, however, the following reference.)... 

Trimethoprim, however, is a competitive inhibitor of dihydrofolate reductase . The accumulation of dihydrofolate, through continuing biosynthesis and reoxidation of tetrahydrofolate, tends to increase the metabolite antimetabolite ratio and diminishes the effectiveness of the blockade. Conjoint application of a sulfonamide, however, removes the source of new dlhydrofolate and Improves the effectiveness of the inhibition. In practice the simultaneous use of the 2 inhibitors results in a 5-10-fold potentiation, broadening of the spectrum of action, a decreased liability to the development of resistance, and a conversion of bacteriostatic to bactericidal effects . 

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