Design, synthesis, and computational affinity prediction of ester soft drugs as inhibitors of dihydrofolate reductase from Pneumocystis carinii

Malin Graffner-Nordberg, Karin Kolmodin, Johan Åqvist, Sherry F. Queener, Anders Hallberg

Research output: Contribution to journalArticle

20 Scopus citations


A series of dihydrofolate reductase (DHFR) inhibitors, where the methylenamino-bridge of non-classical inhibitors was replaced with an ester function, have been prepared as potential soft drugs intended for inhalation against Pneumocystis carinii pneumonia (PCP). Several of the new ester-based inhibitors that should serve as good substrates for the ubiquitous esterases and possibly constitute safer alternatives to metabolically stable DHFR inhibitors administered orally, were found to be potent inhibitors of P. carinii DHFR (pcDHFR). Although the objectives of the present program is to achieve a favorable toxicity profile by applying the soft drug concept, a high preference for inhibition of the fungal DHFR versus the mammalian DHFR is still desirable to suppress host toxicity at the site of administration. Compounds with a slight preference for the fungal enzyme were identified. The selection of the target compounds for synthesis was partly guided by an automated docking and scoring procedure as well as molecular dynamics simulations. The modest selectivity of the synthesized inhibitors was reasonably well predicted, although a correct ranking of the relative affinities was not successful in all cases.

Original languageEnglish (US)
Pages (from-to)43-54
Number of pages12
JournalEuropean Journal of Pharmaceutical Sciences
Issue number1
StatePublished - May 2004



  • Dihydrofolate reductase
  • Molecular dynamics
  • Pneumocystis carinii
  • Soft drug

ASJC Scopus subject areas

  • Pharmaceutical Science

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