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Structural characterization of inhibitors with selectivity against members of a homologous enzyme family.

Pavlovsky AG, Liu X, Faehnle CR, Potente N, Viola RE
Chem Biol Drug Des 79 128-36 (2012)
Related entries: 3pws, 3pyl, 3pyx, 3pzb, 3pzr, 3q0e, 3q11, 3q1l

Cited: 13 times
EuropePMC logo PMID: 22039970

Abstract

The aspartate biosynthetic pathway provides essential metabolites for many important biological functions, including the production of four essential amino acids. As this critical pathway is only present in plants and microbes, any disruptions will be fatal to these organisms. An early pathway enzyme, l-aspartate-β-semialdehyde dehydrogenase, produces a key intermediate at the first branch point of this pathway. Developing potent and selective inhibitors against several orthologs in the l-aspartate-β-semialdehyde dehydrogenase family can serve as lead compounds for antibiotic development. Kinetic studies of two small molecule fragment libraries have identified inhibitors that show good selectivity against l-aspartate-β-semialdehyde dehydrogenases from two different bacterial species, Streptococcus pneumoniae and Vibrio cholerae, despite the presence of an identical constellation of active site amino acids in this homologous enzyme family. Structural characterization of enzyme-inhibitor complexes have elucidated different modes of binding between these structurally related enzymes. This information provides the basis for a structure-guided approach to the development of more potent and more selective inhibitors.

Articles - 3pwk mentioned but not cited (1)

  1. Structural characterization of inhibitors with selectivity against members of a homologous enzyme family. Pavlovsky AG, Liu X, Faehnle CR, Potente N, Viola RE. Chem Biol Drug Des 79 128-136 (2012)


Reviews citing this publication (2)

  1. Cysteamine revisited: repair of arginine to cysteine mutations. Gallego-Villar L, Hannibal L, Häberle J, Thöny B, Ben-Omran T, Nasrallah GK, Dewik AN, Kruger WD, Blom HJ. J Inherit Metab Dis 40 555-567 (2017)
  2. Exploitation of physiology and metabolomics to identify pneumococcal vaccine candidates. Schulz C, Hammerschmidt S. Expert Rev Vaccines 12 1061-1075 (2013)

Articles citing this publication (10)

  1. Structures of ternary complexes of aspartate-semialdehyde dehydrogenase (Rv3708c) from Mycobacterium tuberculosis H37Rv. Vyas R, Tewari R, Weiss MS, Karthikeyan S. Acta Crystallogr D Biol Crystallogr 68 671-679 (2012)
  2. Molecular docking and enzymatic evaluation to identify selective inhibitors of aspartate semialdehyde dehydrogenase. Luniwal A, Wang L, Pavlovsky A, Erhardt PW, Viola RE. Bioorg Med Chem 20 2950-2956 (2012)
  3. Elaboration of a fragment library hit produces potent and selective aspartate semialdehyde dehydrogenase inhibitors. Thangavelu B, Bhansali P, Viola RE. Bioorg Med Chem 23 6622-6631 (2015)
  4. Molecular Modeling and Active Site Binding Mode Characterization of Aspartate β-Semialdehyde Dehydrogenase Family. Kumar R, Garg P. Mol Inform 32 377-383 (2013)
  5. PLK1-dependent phosphorylation restrains EBNA2 activity and lymphomagenesis in EBV-infected mice. Zhang X, Schuhmachers P, Mourão A, Giansanti P, Murer A, Thumann S, Kuklik-Roos C, Beer S, Hauck SM, Hammerschmidt W, Küppers R, Kuster B, Raab M, Strebhardt K, Sattler M, Münz C, Kempkes B. EMBO Rep 22 e53007 (2021)
  6. Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site. Chaton CT, Rodriguez ES, Reed RW, Li J, Kenner CW, Korotkov KV. Sci Rep 9 20267 (2019)
  7. A Fragment Library Screening Approach to Identify Selective Inhibitors against an Essential Fungal Enzyme. Dahal GP, Viola RE. SLAS Discov 23 520-531 (2018)
  8. A cautionary tale of structure-guided inhibitor development against an essential enzyme in the aspartate-biosynthetic pathway. Pavlovsky AG, Thangavelu B, Bhansali P, Viola RE. Acta Crystallogr D Biol Crystallogr 70 3244-3252 (2014)
  9. Structural characterization of aspartate-semialdehyde dehydrogenase from Pseudomonas aeruginosa and Neisseria gonorrhoeae. Teakel SL, Fairman JW, Muruthi MM, Abendroth J, Dranow DM, Lorimer DD, Myler PJ, Edwards TE, Forwood JK. Sci Rep 12 14010 (2022)
  10. Virtual Screening of compounds from Tabernaemontana divaricata for potential anti-bacterial activity. Gogoi RR, Gogoi D, Bezbaruah RL. Bioinformation 10 152-156 (2014)


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