ArticleJournal of medicinal chemistry2001
Adenosine analogues as selective inhibitors of glyceraldehyde-3-phosphate dehydrogenase of Trypanosomatidae via structure-based drug design.
Article in Journal of medicinal chemistry, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 103 citations in OpenAlex.
- Iron Uptake ControlsAntioxidants (Basel, Switzerland) · 2023Article
- Prediction of Antileishmanial Compounds: General Model, Preparation, and Evaluation of 2-Acylpyrrole Derivatives.Journal of chemical information and modeling · 2022Article
- Synthesis of Oligoribonucleotides Containing a 2'-Amino-5'-The Journal of organic chemistry · 2021Article
- Discovery of Novel TASK-3 Channel Blockers Using a Pharmacophore-Based Virtual Screening.International journal of molecular sciences · 2019Article
- The Antimicrobials Anacardic Acid and Curcumin Are Not-Competitive Inhibitors of Gram-Positive Bacterial Pathogenic Glyceraldehyde-3-Phosphate Dehydrogenase by a Mechanism Unrelated to Human C5a Anaphylatoxin Binding.Frontiers in microbiology · 2019Article
- Crystal Structure of Glyceraldehyde-3-Phosphate Dehydrogenase from the Gram-Positive Bacterial PathogenFrontiers in microbiology · 2017Article
- Computational Methods Applied to Rational Drug Design.The open medicinal chemistry journal · 2016Article
- Trypanosoma brucei adenine-phosphoribosyltransferases mediate adenine salvage and aminopurinol susceptibility but not adenine toxicity.International journal for parasitology. Drugs and drug resistance · 2014Article
- Pattern recognition techniques applied to the study of leishmanial glyceraldehyde-3-phosphate dehydrogenase inhibition.International journal of molecular sciences · 2014Article
- Proteome scale comparative modeling for conserved drug and vaccine targets identification in Corynebacterium pseudotuberculosis.BMC genomics · 2014Article
- Identification of electronic and structural descriptors of adenosine analogues related to inhibition of leishmanial glyceraldehyde-3-phosphate dehydrogenase.Molecules (Basel, Switzerland) · 2013Article
- Anticancer agents that counteract tumor glycolysis.ChemMedChem · 2012Review
- Shikimic acid: review of its analytical, isolation, and purification techniques from plant and microbial sources.Journal of chemical biology · 2012Article
- Parallel synthesis of a series of non-functional ATP/NAD analogs with activity against trypanosomatid parasites.Molecular diversity · 2010Article
- Structure of insoluble rat sperm glyceraldehyde-3-phosphate dehydrogenase (GAPDH) via heterotetramer formation with Escherichia coli GAPDH reveals target for contraceptive design.The Journal of biological chemistry · 2009Article
- An unexpected phosphate binding site in glyceraldehyde 3-phosphate dehydrogenase: crystal structures of apo, holo and ternary complex of Cryptosporidium parvum enzyme.BMC structural biology · 2009Article
- Wanted: unique names for unique atom positions. PDB-wide analysis of diastereotopic atom names of small molecules containing diphosphate.BMC bioinformatics · 2008Article
- 2,N6-disubstituted adenosine analogs with antitrypanosomal and antimalarial activities.Antimicrobial agents and chemotherapy · 2007Article
- Hydrolysis products of cAMP analogs cause transformation of Trypanosoma brucei from slender to stumpy-like forms.Proceedings of the National Academy of Sciences of the United States of America · 2006Article
- Combinatorial chemistry as a new approach in antiparasitic drug discovery.Parasitology research · 2003Review
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
In our continuation of the structure-based design of anti-trypanosomatid drugs, parasite-selective adenosine analogues were identified as low micromolar inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Crystal structures of Trypanosoma brucei, Trypanosoma cruzi, Leishmania mexicana, and human GAPDH's provided details of how the adenosyl moiety of NAD(+) interacts with the proteins, and this facilitated the understanding of the relative affinities of a series of adenosine analogues for the various GAPDH's. From exploration of modifications of the naphthalenemethyl and benzamide substituents of a lead compound, N(6)-(1-naphthalenemethyl)-2'-deoxy-2'-(3-methoxybenzamido)adenosine (6e), N(6)-(substituted-naphthalenemethyl)-2'-deoxy-2'-(substituted-benzamido)adenosine analogues were investigated. N(6)-(1-Naphthalenemethyl)-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (6m), N(6)-[1-(3-hydroxynaphthalene)methyl]-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (7m), N(6)-[1-(3-methoxynaphthalene)methyl]-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (9m), N(6)-(2-naphthalenemethyl)-2'-deoxy-2'-(3-methoxybenzamido)adenosine (11e), and N(6)-(2-naphthalenemethyl)-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (11m) demonstrated a 2- to 3-fold improvement over 6e and a 7100- to 25000-fold improvement over the adenosine template. IC(50)'s of these compounds were in the range 2-12 microM for T. brucei, T. cruzi, and L. mexicana GAPDH's, and these compounds did not inhibit mammalian GAPDH when tested at their solubility limit. To explore more thoroughly the structure-activity relationships of this class of compounds, a library of 240 N(6)-(substituted)-2'-deoxy-2'-(amido)adenosine analogues was generated using parallel solution-phase synthesis with N(6) and C2' substituents chosen on the basis of computational docking scores. This resulted in the identification of 40 additional compounds that inhibit parasite GAPDH's in the low micromolar range. We also explored adenosine analogues containing 5'-amido substituents and found that 2',5'-dideoxy-2'-(3,5-dimethoxybenzamido)-5'-(diphenylacetamido)adenosine (49) displays an IC(50) of 60-100 microM against the three parasite GAPDH's.
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