Design, synthesis, computational prediction, and biological evaluation of ester soft drugs as inhibitors of dihydrofolate reductase from pneumocystis carinii

M. Graffner-Nordberg, K. Kolmodin, J. Åqvist, Sherry Queener, A. Hallberg

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

A series of lipophilic soft drugs structurally related to the nonclassical dihydrofolate reductase (DHFR) inhibitors trimetrexate and piritrexim have been designed, synthesized, and evaluated in DHFR assays, with special emphasis on the inhibition of P. carinii DHFR. The best inhibitors, encompassing an ester bond in the bridge connecting the two aromatic systems, were approximately 10 times less potent than trimetrexate and piritrexim. The metabolites were designed to be poor inhibitors. Furthermore, molecular dynamics simulations of three ligands in complex with DHFR from Pneumocystis carinii and from the human enzyme were conducted in order to better understand the factors determining the selectivity. A correct ranking of the relative inhibition of DHFR was achieved utilizing the linear interaction energy method. The soft drugs are intended for local administration. One representative ester was selected for a pharmacokinetic study in rats where it was found to undergo fast metabolic degradation to the predicted inactive metabolites.

Original languageEnglish
Pages (from-to)2391-2402
Number of pages12
JournalJournal of Medicinal Chemistry
Volume44
Issue number15
DOIs
StatePublished - Jul 19 2001

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Folic Acid Antagonists
Pneumocystis carinii
Tetrahydrofolate Dehydrogenase
Esters
Trimetrexate
Metabolites
Pharmaceutical Preparations
Pharmacokinetics
Molecular Dynamics Simulation
Molecular dynamics
Rats
Assays
Ligands
Degradation
Computer simulation
Enzymes
piritrexim

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Design, synthesis, computational prediction, and biological evaluation of ester soft drugs as inhibitors of dihydrofolate reductase from pneumocystis carinii. / Graffner-Nordberg, M.; Kolmodin, K.; Åqvist, J.; Queener, Sherry; Hallberg, A.

In: Journal of Medicinal Chemistry, Vol. 44, No. 15, 19.07.2001, p. 2391-2402.

Research output: Contribution to journalArticle

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