title: Design, synthesis, and computational affinity prediction of ester soft drugs as inhibitors of dihydrofolate reductase from Pneumocystis carinii.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Graffner-Nordberg
authors.forename: Karin
authors.initials: K
authors.lastname: Kolmodin
authors.forename: Johan
authors.initials: J
authors.lastname: Aqvist
authors.forename: Sherry F
authors.initials: SF
authors.lastname: Queener
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
mesh_terms: D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D045363:Pneumocystis carinii / Q000201:enzymology*; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry
chemical_list: D004952:Esters; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase