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Structural studies of pterin-based inhibitors of dihydropteroate synthase.

Hevener KE, Yun MK, Qi J, Kerr ID, Babaoglu K, Hurdle JG, Balakrishna K, White SW, Lee RE
J Med Chem 53 166-77 (2010)
Related entries: 3h22, 3h23, 3h24, 3h26, 3h2a, 3h2c, 3h2e, 3h2f, 3h2m, 3h2n, 3h2o

Cited: 35 times
EuropePMC logo PMID: 19899766

Abstract

Dihydropteroate synthase (DHPS) is a key enzyme in bacterial folate synthesis and the target of the sulfonamide class of antibacterials. Resistance and toxicities associated with sulfonamides have led to a decrease in their clinical use. Compounds that bind to the pterin binding site of DHPS, as opposed to the p-amino benzoic acid (pABA) binding site targeted by the sulfonamide agents, are anticipated to bypass sulfonamide resistance. To identify such inhibitors and map the pterin binding pocket, we have performed virtual screening, synthetic, and structural studies using Bacillus anthracis DHPS. Several compounds with inhibitory activity have been identified, and crystal structures have been determined that show how the compounds engage the pterin site. The structural studies identify the key binding elements and have been used to generate a structure-activity based pharmacophore map that will facilitate the development of the next generation of DHPS inhibitors which specifically target the pterin site.

Articles - 3h21 mentioned but not cited (1)

  1. Structural studies of pterin-based inhibitors of dihydropteroate synthase. Hevener KE, Yun MK, Qi J, Kerr ID, Babaoglu K, Hurdle JG, Balakrishna K, White SW, Lee RE. J Med Chem 53 166-177 (2010)


Reviews citing this publication (8)

  1. Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery. Bourne CR. Antibiotics (Basel) 3 1-28 (2014)
  2. Bioorganometallic chemistry with IspG and IspH: structure, function, and inhibition of the [Fe(4)S(4)] proteins involved in isoprenoid biosynthesis. Wang W, Oldfield E. Angew Chem Int Ed Engl 53 4294-4310 (2014)
  3. Replacing sulfa drugs with novel DHPS inhibitors. Hammoudeh DI, Zhao Y, White SW, Lee RE. Future Med Chem 5 1331-1340 (2013)
  4. Folate biosynthesis pathway: mechanisms and insights into drug design for infectious diseases. Bertacine Dias MV, Santos JC, Libreros-Zúñiga GA, Ribeiro JA, Chavez-Pacheco SM. Future Med Chem 10 935-959 (2018)
  5. New developments in vaccines, inhibitors of anthrax toxins, and antibiotic therapeutics for Bacillus anthracis. Beierlein JM, Anderson AC. Curr Med Chem 18 5083-5094 (2011)
  6. Antibacterial Antifolates: From Development through Resistance to the Next Generation. Estrada A, Wright DL, Anderson AC. Cold Spring Harb Perspect Med 6 a028324 (2016)
  7. Therapeutic potential of pteridine derivatives: A comprehensive review. Carmona-Martínez V, Ruiz-Alcaraz AJ, Vera M, Guirado A, Martínez-Esparza M, García-Peñarrubia P. Med Res Rev 39 461-516 (2019)
  8. Revitalizing antifolates through understanding mechanisms that govern susceptibility and resistance. Kordus SL, Baughn AD. Medchemcomm 10 880-895 (2019)

Articles citing this publication (26)

  1. Catalysis and sulfa drug resistance in dihydropteroate synthase. Yun MK, Wu Y, Li Z, Zhao Y, Waddell MB, Ferreira AM, Lee RE, Bashford D, White SW. Science 335 1110-1114 (2012)
  2. Crystal structure of the 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase•dihydropteroate synthase bifunctional enzyme from Francisella tularensis. Pemble CW, Mehta PK, Mehra S, Li Z, Nourse A, Lee RE, White SW. PLoS One 5 e14165 (2010)
  3. Structure of S. aureus HPPK and the discovery of a new substrate site inhibitor. Chhabra S, Dolezal O, Collins BM, Newman J, Simpson JS, Macreadie IG, Fernley R, Peat TS, Swarbrick JD. PLoS One 7 e29444 (2012)
  4. 8-Mercaptoguanine Derivatives as Inhibitors of Dihydropteroate Synthase. Dennis ML, Lee MD, Harjani JR, Ahmed M, DeBono AJ, Pitcher NP, Wang ZC, Chhabra S, Barlow N, Rahmani R, Cleary B, Dolezal O, Hattarki M, Aurelio L, Shonberg J, Graham B, Peat TS, Baell JB, Swarbrick JD. Chemistry 24 1922-1930 (2018)
  5. Design, Synthesis, and Antimicrobial Evaluation of a New Series of N-Sulfonamide 2-Pyridones as Dual Inhibitors of DHPS and DHFR Enzymes. Azzam RA, Elsayed RE, Elgemeie GH. ACS Omega 5 10401-10414 (2020)
  6. Structure-based design of novel pyrimido[4,5-c]pyridazine derivatives as dihydropteroate synthase inhibitors with increased affinity. Zhao Y, Hammoudeh D, Yun MK, Qi J, White SW, Lee RE. ChemMedChem 7 861-870 (2012)
  7. Exploring the chemical space around 8-mercaptoguanine as a route to new inhibitors of the folate biosynthesis enzyme HPPK. Chhabra S, Barlow N, Dolezal O, Hattarki MK, Newman J, Peat TS, Graham B, Swarbrick JD. PLoS One 8 e59535 (2013)
  8. Identification and characterization of an allosteric inhibitory site on dihydropteroate synthase. Hammoudeh DI, Daté M, Yun MK, Zhang W, Boyd VA, Viacava Follis A, Griffith E, Lee RE, Bashford D, White SW. ACS Chem Biol 9 1294-1302 (2014)
  9. The identification, analysis and structure-based development of novel inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase. Yun MK, Hoagland D, Kumar G, Waddell MB, Rock CO, Lee RE, White SW. Bioorg Med Chem 22 2157-2165 (2014)
  10. Crystal structures of Burkholderia cenocepacia dihydropteroate synthase in the apo-form and complexed with the product 7,8-dihydropteroate. Morgan RE, Batot GO, Dement JM, Rao VA, Eadsforth TC, Hunter WN. BMC Struct Biol 11 21 (2011)
  11. Influence of Sulfonamide Contamination Derived from Veterinary Antibiotics on Plant Growth and Development. Cheong MS, Seo KH, Chohra H, Yoon YE, Choe H, Kantharaj V, Lee YB. Antibiotics (Basel) 9 E456 (2020)
  12. Structural enzymology and inhibition of the bi-functional folate pathway enzyme HPPK-DHPS from the biowarfare agent Francisella tularensis. Shaw GX, Li Y, Shi G, Wu Y, Cherry S, Needle D, Zhang D, Tropea JE, Waugh DS, Yan H, Ji X. FEBS J 281 4123-4137 (2014)
  13. Synthesis of bi-substrate state mimics of dihydropteroate synthase as potential inhibitors and molecular probes. Qi J, Virga KG, Das S, Zhao Y, Yun MK, White SW, Lee RE. Bioorg Med Chem 19 1298-1305 (2011)
  14. GC-MS analysis and molecular docking of bioactive compounds of Camellia sinensis and Camellia assamica. Pradhan S, Dubey RC. Arch Microbiol 203 2501-2510 (2021)
  15. RepTB: a gene ontology based drug repurposing approach for tuberculosis. Passi A, Rajput NK, Wild DJ, Bhardwaj A. J Cheminform 10 24 (2018)
  16. Development of a pterin-based fluorescent probe for screening dihydropteroate synthase. Zhao Y, Hammoudeh D, Lin W, Das S, Yun MK, Li Z, Griffith E, Chen T, White SW, Lee RE. Bioconjug Chem 22 2110-2117 (2011)
  17. Exploring the catalytic mechanism of dihydropteroate synthase: elucidating the differences between the substrate and inhibitor. Chotpatiwetchkul W, Boonyarattanakalin K, Gleeson D, Gleeson MP. Org Biomol Chem 15 5593-5601 (2017)
  18. Identification of Growth Inhibitors of the Fish Pathogen Saprolegnia parasitica Using in silico Subtractive Proteomics, Computational Modeling, and Biochemical Validation. Kumar S, Mandal RS, Bulone V, Srivastava V. Front Microbiol 11 571093 (2020)
  19. Identification and age-dependence of pteridines in bed bugs (Cimex lectularius) and bat bugs (C. pipistrelli) using liquid chromatography-tandem mass spectrometry. Křemenová J, Balvín O, Otti O, Pavonič M, Reinhardt K, Šimek Z, Bartonička T. Sci Rep 10 10146 (2020)
  20. Insights into the drug resistance induced by the BaDHPS mutations: molecular dynamic simulations and MM/GBSA studies. Chu WT, Zhang JL, Zheng QC, Chen L, Xue Q, Zhang HX. J Biomol Struct Dyn 31 1127-1136 (2013)
  21. Synthesis of pyrazolo-1,2,4-triazolo[4,3-a]quinoxalines as antimicrobial agents with potential inhibition of DHPS enzyme. Z El-Attar MA, Elbayaa RY, Shaaban OG, Habib NS, Abdel Wahab AE, Abdelwahab IA, M El-Hawash SA. Future Med Chem 10 2155-2175 (2018)
  22. Assay Development and Identification of the First Plasmodium falciparum 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase Inhibitors. Hoarau M, Suwanakitti N, Varatthan T, Thiabma R, Rattanajak R, Charoensetakul N, Redman EK, Khotavivattana T, Vilaivan T, Yuthavong Y, Kamchonwongpaisan S. Molecules 27 3515 (2022)
  23. Crystal structure of Arabidopsis thaliana HPPK/DHPS, a bifunctional enzyme and target of the herbicide asulam. Vadlamani G, Sukhoverkov KV, Haywood J, Breese KJ, Fisher MF, Stubbs KA, Bond CS, Mylne JS. Plant Commun 3 100322 (2022)
  24. Molecular mechanism of plasmid-borne resistance to sulfonamide antibiotics. Venkatesan M, Fruci M, Verellen LA, Skarina T, Mesa N, Flick R, Pham C, Mahadevan R, Stogios PJ, Savchenko A. Nat Commun 14 4031 (2023)
  25. Synthesis, Physicochemical Properties and Molecular Docking of New Benzothiazole Derivatives as Antimicrobial Agents Targeting DHPS Enzyme. Azzam RA, Elboshi HA, Elgemeie GH. Antibiotics (Basel) 11 1799 (2022)
  26. Synthesis, Structure, Hirshfeld Surface Analysis, Non-Covalent Interaction, and In Silico Studies of 4-Hydroxy-1-[(4-Nitrophenyl)Sulfonyl]Pyrrolidine-2-Carboxyllic Acid. Ugwu DI, Eze FU, Ezeorah CJ, Rhyman L, Ramasami P, Tania G, Eze CC, Uzoewulu CP, Ogboo BC, Okpareke OC. J Chem Crystallogr 1-14 (2023)


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