Structure–activity correlations for three pyrido[2,3-d]pyrimidine antifolates binding to human and Pneumocystis carinii dihydrofolate reductase

To further define the interactions that enhance the selectivity of binding and to directly compare the binding of the most potent analogue {N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine; compound 26} in the series of bicyclic pyrido[2,3-d]pyrimidine analogues of piritrexim (PTX) with native human (h), Pneumocystis carinii (pc) and Pneumocystis jirovecii (pj) dihydrofolate reductase (DHFR) enzymes, the crystal structures of hDHFR complexed with N6-methyl-N6-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine (compound 22), of hDHFR complexed with compound 26 and of pcDHFR complexed with N6-methyl-N6-1-naphthylpyrido[2,3-d]pyrimidine-2,4,6-triamine (compound 24) are reported as ternary complexes with NADPH. This series of bicyclic pyrido[2,3-d]pyrimidines were designed in which there was a transposition of the 5-methyl group of PTX to the N9 position of the pyrido[2,3-d]pyrimidine. It was hypothesized that the N9-methyl group would preferentially interact with Ile123 of pcDHFR (and Ile123 of pjDHFR), but not with the shorter Val115 in hDHFR. Structure–activity data for this series of antifolates revealed that a trifluoro derivative (26) was the most selective against pjDHFR compared with mammalian DHFR (h/pj = 35.7). Structural data for the hDHFR–26 complex revealed that 26 binds in a different conformation from that observed in the pcDHFR–26 complex. In the hDHFR–26 complex the trifluorophenyl ring of 26 occupies a position near the c...

Source: Acta Crystallographica Section F - May 27, 2015 Category: Biochemistry Authors: Cody, V.Pace, J.Namjoshi, O.A.Gangjee, A. Tags: dihydrofolate reductase Pneumocystis carinii pathogens antifolate inhibitors conformational analysis research communications Source Type: research