Antifolate agents: a patent review (2006 – 2010)

Wright, Dennis L.; Anderson, Amy C.

doi:10.1517/13543776.2011.587804

Cited by 32 publications

(31 citation statements)

References 34 publications

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“…The next four positions (18)(19)(20)(21) correspond to residues on the same loop as the PEKN insertion, connecting helix aII to strand b C . Positions 18 and 19 were seen to have positively charged residues and proline, respectively, in most species, whereas residues at positions 20 and 21 were seen to belong to more than two chemical types (Figs 3 and S1).…”

Section: Structural Signaturesmentioning

confidence: 99%

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Structural analysis of dihydrofolate reductases enables rationalization of antifolate binding affinities and suggests repurposing possibilities

Bhosle

Chandra

2016

The FEBS Journal

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Antifolates are competitive inhibitors of dihydrofolate reductase (DHFR), a conserved enzyme that is central to metabolism and widely targeted in pathogenic diseases, cancer and autoimmune disorders. Although most clinically used antifolates are known to be target specific, some display a fair degree of cross-reactivity with DHFRs from other species. A method that enables identification of determinants of affinity and specificity in target DHFRs from different species and provides guidelines for the design of antifolates is currently lacking. To address this, we first captured the potential druggable space of a DHFR in a substructure called the 'supersite' and classified supersites of DHFRs from 56 species into 16 'site-types' based on pairwise structural similarity. Analysis of supersites across these site-types revealed that DHFRs exhibit varying extents of dissimilarity at structurally equivalent positions in and around the binding site. We were able to explain the pattern of affinities towards chemically diverse antifolates exhibited by DHFRs of different site-types based on these structural differences. We then generated an antifolate-DHFR network by mapping known high-affinity antifolates to their respective supersites and used this to identify antifolates that can be repurposed based on similarity between supersites or antifolates. Thus, we identified 177 human-specific and 458 pathogen-specific antifolates, a large number of which are supported by available experimental data. Thus, in the light of the clinical importance of DHFR, we present a novel approach to identifying differences in the druggable space of DHFRs that can be utilized for rational design of antifolates.

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Section: Structural Signaturesmentioning

confidence: 99%

“…Positions 2-7 in the alignment belong to the Met20 loop (loop 1) of DHFR (E. coli DHFR: 9-24, human DHFR: [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]). This loop lies over the active site and regulates entry and exit of the substrate, product and Note: Only first author and year are provided for each reference.…”

Section: M20 Loopmentioning

confidence: 99%

Structural analysis of dihydrofolate reductases enables rationalization of antifolate binding affinities and suggests repurposing possibilities

Bhosle

Chandra

2016

The FEBS Journal

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“…Aside from the scaffold described herein and also previously by Basilea Pharmaceutica Ltd. [6, 7], other anti-DHFR compounds under development include Iclaprim, being pursued by Acino Pharma [8], AR-709, pursued by Evolva [9], and 7-aryl-2,4-diaminoquinazolines, pursued by Trius Therapeutics [10]. A review of recent patent literature outlined antibacterial efforts targeting DHFR specifically for bacteria relevant to human health, including Staphylococcus aureus, Pneumocystis carinii and B. anthracis [11]. …”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationship for enantiomers of potent inhibitors of B. anthracis dihydrofolate reductase

Wakeham

Nammalwar

Tseitin

et al. 2013

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Background Bacterial resistance to antibiotic therapies is increasing and new treatment options are badly needed. There is an overlap between these resistant bacteria and organisms classified as likely bioterror weapons. For example, Bacillus anthracis is innately resistant to the anti-folate trimethoprim due to sequence changes found in the dihydrofolate reductase enzyme. Development of new inhibitors provides an opportunity to enhance the current arsenal of anti-folate antibiotics while also expanding the coverage of the anti-folate class. Methods We have characterized inhibitors of Bacillus anthracis dihydrofolate reductase by measuring the Ki and MIC values and calculating the energetics of binding. This series contains a core diaminopyrimidine ring, a central dimethoxybenzyl ring, and a dihydrophthalazine moiety. We have altered the chemical groups extended from a chiral center on the dihydropyridazine ring of the phthalazine moiety. The interactions for the most potent compounds were visualized by X-ray structure determination. Results We find that the potency of individual enantiomers is divergent with clear preference for the S-enantiomer, while maintaining a high conservation of contacts within the binding site. The preference for enantiomers seems to be predicated largely by differential interactions with protein residues Leu29, Gln30 and Arg53. Conclusions These studies have clarified the activity of modifications and of individual enantiomers, and highlighted the role of the less-active R-enantiomer in effectively diluting the more active S-enantiomer in racemic solutions. This directly contributes to the development of new antimicrobials, combating trimethoprim resistance, and treatment options for potential bioterrorism agents.

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“…1 It has been proposed that DHNA represents a promising new target for the development of antibacterials, underlying the importance of studying the catalytic and chemical mechanism of this enzyme in pathogenic bacteria such as Mycobacterium tuberculosis , the causative agent of tuberculosis. 2,3 DHNAs are interesting enzymes since they catalyze the cleavage of a carbon-carbon bond without the requirement of metals or cofactors, being considered a unique type of aldolase in which a substrate imbedded imine assists in catalysis.…”

Section: Introductionmentioning

confidence: 99%

One Substrate, Five Products: Reactions Catalyzed by the Dihydroneopterin Aldolase from Mycobacterium tuberculosis

Czekster

Blanchard

2012

J. Am. Chem. Soc.

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Tetrahydrofolate cofactors are required for one carbon transfer reactions involved in the synthesis of purines, amino acids, and thymidine. Inhibition of tetrahydrofolate biosynthesis is a powerful therapeutic strategy in the treatment of several diseases, and the possibility of using antifolates to inhibit enzymes from Mycobacterium tuberculosis has been explored. This work focuses on the study of the first enzyme in tetrahydrofolate biosynthesis that is unique to bacteria, dihydroneopterin aldolase (MtDHNA). This enzyme requires no metals or cofactors, and does not form a protein mediated Schiff base with the substrate, unlike most aldolases. Here, we were able to demonstrate that the reaction catalyzed by MtDHNA generates three different pterin products, one of which is not produced by other wild type DHNAs. The enzyme-substrate complex partitions 51% in the first turnover to form the aldolase product, 24% to the epimerase product, and 25% to the oxygenase product. The aldolase reaction is strongly pH-dependent, and apparent pKa values were obtained for the first time for this class of enzyme. Furthermore, chemistry is rate-limiting for the aldolase reaction, and the analysis of solvent kinetic isotope effects in steady-state and pre-steady-state conditions, combined with proton inventory studies revealed that two protons and a likely solvent contribution are involved in formation and breakage of a common intermediate. This study provides information about the plasticity required from a catalyst that possesses high substrate specificity while being capable of utilizing two distinct epimers with the same efficiency to generate five distinct products.

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Antifolate agents: a patent review (2006 – 2010)

Cited by 32 publications

References 34 publications

Structural analysis of dihydrofolate reductases enables rationalization of antifolate binding affinities and suggests repurposing possibilities

Structural analysis of dihydrofolate reductases enables rationalization of antifolate binding affinities and suggests repurposing possibilities

Structure–activity relationship for enantiomers of potent inhibitors of B. anthracis dihydrofolate reductase

One Substrate, Five Products: Reactions Catalyzed by the Dihydroneopterin Aldolase from Mycobacterium tuberculosis

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