Receptor-based design of dihydrofolate reductase inhibitors: comparison of crystallographically determined enzyme binding with enzyme affinity in a series of carboxy-substituted trimethoprim analogs

Kuyper, Lee F.; Roth, Barbara; Baccanari, David P.; Ferone, Robert; Beddell, C.R.; Champness, J.N.; Stammers, D.K.; Dann, J. G.; Norrington, F. E.

doi:10.1021/jm00352a002

Cited by 87 publications

(39 citation statements)

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“…Packing in small molecule crystal structures of arginine and carboxyl amino acaids reveals no clear preference for typel interactions over type2 [15][16][17]. However, quantum mechanical calculations on methylguanidinium-carboxylate suggest an energetic favourability for typel.…”

Section: Discussionmentioning

confidence: 94%

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The geometries of interacting arginine‐carboxyls in proteins

et al. 1987

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The geometries are reported for interacting arginine-carboxyl pairs obtained from 37 high resolution protein structures solved to a resolution of 2.0 A or better. The closest interatomic distance between the guanidinium and carboxyl is less than 4.2 A for 74 arginine and carboxyl groups, with the majority of these lying within hydrogen-bonding distance (2.6-3.0 A). Interacting pairs have been transformed into a common orientation, and arginine-carboxyl, and carboxyl-arginine geometries have been calculated. This has been defined in terms of the spherical polar angles TO, T~o, and the angle P, between the guanidinium and carboxyl planes. Results show a clear preference for the guanidinium and carboxyl groups to be approximately coplanar, and for the carboxyl oxygens to hydrogen bond with the guanidinium nitrogens. Single nitrogensingle oxygen is the most common type of interaction, however twin nitrogen-twin oxygen interactions also occur frequently. The majority of these occur between the carboxyl oxygens and the NH 1 and NE atoms of the arginine, and are only rarely observed for NH 1 and NH2. The information presented may be of use in the modelling of arginine-carboxyl interactions within proteins.

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Section: Discussionmentioning

confidence: 94%

“…There are few high resolution crystallographic structures of enzyme-inhibitor/substrate complexes which involve arginine-carboxyl interactions [13][14][15]. However in both trypsinogen complexed with bovine pancreatic trypsin inhibitor, and dihydrofolate reductase bound with a trimethoprim analogue, a type2 interaction is seen.…”

Section: Discussionmentioning

confidence: 99%

The geometries of interacting arginine‐carboxyls in proteins

et al. 1987

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“…These data revealed conformational flexibility in the inhibitor orientation bound to both human and pcDHFR and further showed that only one of the stereo isomers of the racemic mixture bound to DHFR [71]. In the pcDHFR data, there were two orientations found for the indoline Structural characteristics of antifolate DHFR enzyme interactions 323 ring, however, they represented different positional isomers, not enantiomorphic configurations of the antifolate.…”

Section: Trimetrexatementioning

confidence: 87%

“…Structural data for these inhibitor complexes with E. coli, mouse (m) and Pneumocystis carinii (pc) DHFR [50,71] revealed that the added interactions of the 3 0 -methoxy substituent in the -glutamate binding pocket enhanced their inhibitory properties. These compounds validate the hypothesis that 2,4-diaminopyrimidines with an extended !-carboxy(alkyloxy) side chain at the 5-position of the trimethoprim (TMP) benzyl ring form favorable interactions with DHFR [71] and in the case of DH3, provide insight into the features that contribute to its 5000-fold enhanced selectivity for pcDHFR compared to the mammalian enzyme. This analysis also showed that the TMP bridge conformation for DH1 was outside the tight cluster observed for DH3 both in pcDHFR and mDHFR, as well as other ternary TMP complexes [50].…”

Section: Structural Characteristics Of Antifolate Dhfr Enzyme Interacmentioning

confidence: 99%

Structural characteristics of antifolate dihydrofolate reductase enzyme interactions

Cody¹,

Schwalbe²

2006

Crystallography Reviews

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The ubiquitous enzyme dihydrofolate reductase (DHFR) is responsible for the reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate in an NADPH-dependent manner. It is also a key pharmacological target for the treatment of cancer, as well as bacterial and opportunistic pathogenic infections. Interest in the design of potent and selective antifolate inhibitors has made DHFR one of the most studied enzymes, in particular its structural and biochemical properties. This review surveys more than 129 DHFR solution and crystal structures currently (02/07) reported in the Protein Data Bank representing 15 species of enzyme. Comparison of these DHFR sequences shows that while there is a high sequence homology among vertebrate species (75-95%), there is only about 30% homology between vertebrate and bacterial species. Despite the highly conserved nature of the ligand and cofactor binding sites, DHFR can bind a wide range of compounds that can have a high degree of flexibility. The enzyme itself can also undergo ligand-induced conformational changes that reflect its catalytic mechanism of action. Mechanistic questions can now be addressed with the structural data available for atomic resolution enzyme complexes as well as from neutron diffraction data that have recently become available. These data provide new insight into the design of novel inhibitors that can target specific species with high selectivity of binding.

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“…To circumvent this problem, alkylation of the anion of 7 was performed with 3-bromopropanoic acid in the presence of an extra 1 equiv of base. The superiority of 3-bromopropanoic acid over methyl 3-bromopropanoate in the O-alkylation of a phenolic OH group is wellknown, and was noted, for example, by Kuyper and coworkers 30 during their synthesis of the trimethoprim…”

Section: Chemistrymentioning

confidence: 92%

Synthesis of 2,4-Diamino-6-[2‘-O-(ω-carboxyalkyl)oxydibenz[b,f]azepin-5-yl]methylpteridines as Potent and Selective Inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium Dihydrofolate Reductase

Rosowsky

Chan

et al. 2004

J. Med. Chem.

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Six previously undescribed N-(2,4-diaminopteridin-6-yl)methyldibenz[b,f]azepines with water-solubilizing O-carboxyalkyloxy or O-carboxybenzyloxy side chains at the 2'-position were synthesized and compared with trimethoprim (TMP) and piritrexim (PTX) as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three of the opportunistic organisms known to cause significant morbidity and mortality in patients with AIDS and other disorders of the immune system. The ability of the new analogues to inhibit reduction of dihydrofolate to tetrahydrofolate by Pc, Tg, Ma, and rat DHFR was determined, and the selectivity index (SI) was calculated from the ratio IC(50)(rat DHFR)/IC(50)(Pc, Tg, or Ma DHFR). The IC(50) values of the 2'-O-carboxypropyl analogue (10), with SI values in parentheses, were 1.1 nM (1300) against Pc DHFR, 9.9 nM (120) against Tg DHFR, and 2.0 nM (600) against Ma DHFR. The corresponding values for the 2'-O-(4-carboxybenzyloxy) analogue (12) were 1.0 nM (560), 22 nM (21), and 0.75 nM (630). By comparison, the IC(50) and SI values for TMP were Pc, 13 000 nM (14); Tg, 2800 nM (65); and Ma, 300 nM (610). For the prototypical potent but nonselective inhibitors PTX and TMX, respectively, these values were Pc, 13 nM (0.26) and 47 nM (0.17); Tg, 4.3 nM (0.76) and 16 nM (0.50); Ma, 0.61 nM (5.4) and 1.5 nM (5.3). Thus 10 and 12 met the criterion for DHFR inhibitors that combine the high selectivity of TMP with the high potency of PTX and TMX.

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Receptor-based design of dihydrofolate reductase inhibitors: comparison of crystallographically determined enzyme binding with enzyme affinity in a series of carboxy-substituted trimethoprim analogs

Cited by 87 publications

References 1 publication

The geometries of interacting arginine‐carboxyls in proteins

The geometries of interacting arginine‐carboxyls in proteins

Structural characteristics of antifolate dihydrofolate reductase enzyme interactions

Synthesis of 2,4-Diamino-6-[2‘-O-(ω-carboxyalkyl)oxydibenz[b,f]azepin-5-yl]methylpteridines as Potent and Selective Inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium Dihydrofolate Reductase

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