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Conformational Aspects in the Design of Inhibitors for Serine Hydroxymethyltransferase (SHMT): Biphenyl, Aryl Sulfonamide, and Aryl Sulfone Motifs.

Schwertz G, Frei MS, Witschel MC, Rottmann M, Leartsakulpanich U, Chitnumsub P, Jaruwat A, Ittarat W, Schäfer A, Aponte RA, Trapp N, Mark K, Chaiyen P, Diederich F
Chemistry 23 14345-14357 (2017)
Related entries: 5xmp, 5xmr, 5xms, 5xmt, 5xmu, 5xmv

Cited: 7 times
EuropePMC logo PMID: 28967982

Abstract

Malaria remains a major threat to mankind due to the perpetual emergence of resistance against marketed drugs. Twenty-one pyrazolopyran-based inhibitors bearing terminal biphenyl, aryl sulfonamide, or aryl sulfone motifs were synthesized and tested towards serine hydroxymethyltransferase (SHMT), a key enzyme of the folate cycle. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target, as well as PfNF54 strains in cell-based assays in the low nanomolar range (18-56 nm). Seven co-crystal structures with P. vivax (Pv) SHMT were solved at 2.2-2.6 Å resolution. We observed an unprecedented influence of the torsion angle of ortho-substituted biphenyl moieties on cell-based efficacy. The peculiar lipophilic character of the sulfonyl moiety was highlighted in the complexes with aryl sulfonamide analogues, which bind in their preferred staggered orientation. The results are discussed within the context of conformational preferences in the ligands.

Reviews citing this publication (2)

  1. Targeting cancer metabolism in the era of precision oncology. Stine ZE, Schug ZT, Salvino JM, Dang CV. Nat Rev Drug Discov 21 141-162 (2022)
  2. Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target. Vicente-Blázquez A, González M, Álvarez R, Del Mazo S, Medarde M, Peláez R. Med Res Rev 39 775-830 (2019)

Articles citing this publication (5)

  1. Chloroplastic Serine Hydroxymethyltransferase From Medicago truncatula: A Structural Characterization. Ruszkowski M, Sekula B, Ruszkowska A, Dauter Z. Front Plant Sci 9 584 (2018)
  2. A flap motif in human serine hydroxymethyltransferase is important for structural stabilization, ligand binding, and control of product release. Ubonprasert S, Jaroensuk J, Pornthanakasem W, Kamonsutthipaijit N, Wongpituk P, Mee-Udorn P, Rungrotmongkol T, Ketchart O, Chitnumsub P, Leartsakulpanich U, Chaiyen P, Maenpuen S. J Biol Chem 294 10490-10502 (2019)
  3. Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold. Schwertz G, Witschel MC, Rottmann M, Leartsakulpanich U, Chitnumsub P, Jaruwat A, Amornwatcharapong W, Ittarat W, Schäfer A, Aponte RA, Trapp N, Chaiyen P, Diederich F. ChemMedChem 13 931-943 (2018)
  4. Impaired folate binding of serine hydroxymethyltransferase 8 from soybean underlies resistance to the soybean cyst nematode. Korasick DA, Kandoth PK, Tanner JJ, Mitchum MG, Beamer LJ. J Biol Chem 295 3708-3718 (2020)
  5. Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models. Ruszkowski M, Sekula B, Ruszkowska A, Contestabile R, Nogues I, Angelaccio S, Szczepaniak A, Dauter Z. Sci Rep 9 19614 (2019)


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