Structural studies on bio-active compounds. Part XV. Structure-activity relationships for pyrimethamine and a series of diaminopyrimidine analogues versus bacterial dihydrofolate reductase.
The phenylpyrimidine derivative pyrimethamine and its congeners inhibit the enzyme dihydrofolate reductase (5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) and are of interest as antiproliferative agents. In this study the equilibrium conformations of some pyrimethamine derivatives, and their interactions with Escherichia coli dihydrofolate reductase, were investigated using molecular modelling techniques. In each case the phenyl ring avoided coplanarity with the pyrimidine ring and attained a position approximately perpendicular to it, in agreement with crystal structures. A meta substituent could be placed either side of the pyrimidine plane, forming two non-equivalent, slowly interconverting solution conformations. Except for meta-azidopyrimethamine, both conformations of all the inhibitors were able to bind to the active site cleft of the enzyme with the diaminopyrimidine moiety, making the normal pattern of enzyme/inhibitor hydrogen bonds. One such conformation of the meta-azido compound failed to bind because of unacceptable steric clashes, whilst the other showed enhanced binding energy attributable to the occupation of a hydrophobic pocket by the azido group. The enhanced binding of 2,4-diamino-6-ethyl-5-phenylpyrimidine over its 6-methyl analogue was also related to attractive hydrophobic interactions.
Sansom
C E
CE
Department of Pharmaceutical Sciences, Aston University, Birmingham, U.K.
Schwalbe
C H
CH
Lambert
P A
PA
Griffin
R J
RJ
Stevens
M F
MF
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003196:Computer Graphics; D004926:Escherichia coli / Q000201:enzymology; D005493:Folic Acid Antagonists; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D011739:Pyrimethamine / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D005493:Folic Acid Antagonists; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine; D011739:Pyrimethamine