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Design, synthesis, and computational affinity prediction of ester soft drugs as inhibitors of dihydrofolate reductase from Pneumocystis carinii
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2004 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 22, no 1, 43-54 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2004. Vol. 22, no 1, 43-54 p.
Keyword [en]
Comparative Study, Drug Design, Drug Evaluation; Preclinical, Esters/*chemical synthesis/*chemistry, Folic Acid Antagonists/*chemical synthesis/*chemistry, Humans, Inhibitory Concentration 50, Models; Molecular, Pneumocystis carinii/*enzymology, Research Support; Non-U.S. Gov't, Tetrahydrofolate Dehydrogenase/chemistry
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-72739DOI: 10.1016/j.ejps.2004.02.004ISI: 000221502500005PubMedID: 15113582OAI: oai:DiVA.org:uu-72739DiVA: diva2:100650
Available from: 2005-05-27 Created: 2005-05-27 Last updated: 2016-06-29

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Graffner-Nordberg, MalinÅqvist, JohanHallberg, Anders
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