title: Computational predictions of binding affinities to dihydrofolate reductase: synthesis and biological evaluation of methotrexate analogues.
abstract: The relative binding affinities to human dihydrofolate reductase of four new potential antifolates, containing ester linkages between the two aromatic systems, were estimated by free energy perturbation simulations. The ester analogue, predicted to exhibit the highest binding affinity to human dihydrofolate reductase, and a reference ester (more structurally related to methotrexate) were synthesized. As deduced from the measured IC(50) values, the calculated ranking of the ligands was correct although a greater difference in affinity was indicated by the experimental measurements. Among the new antifolates the most potent inhibitor exhibited a similar pharmacokinetic profile to methotrexate but lacked activity in a complex antiarthritic model in rat in vivo.
authors.affiliation: Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Graffner-Nordberg
authors.forename: J
authors.initials: J
authors.lastname: Marelius
authors.forename: S
authors.initials: S
authors.lastname: Ohlsson
authors.forename: A
authors.initials: A
authors.lastname: Persson
authors.forename: G
authors.initials: G
authors.lastname: Swedberg
authors.forename: P
authors.initials: P
authors.lastname: Andersson
authors.forename: S E
authors.initials: SE
authors.lastname: Andersson
authors.forename: J
authors.initials: J
authors.lastname: Aqvist
authors.forename: A
authors.initials: A
authors.lastname: Hallberg
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D001682:Biological Availability; D005260:Female; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D011485:Protein Binding; D051381:Rats; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D018501:Antirheumatic Agents; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate