title: Modeling the inhibition of quadruple mutant Plasmodium falciparum dihydrofolate reductase by pyrimethamine derivatives.
abstract: Modeling studies were performed on known inhibitors of the quadruple mutant Plasmodium falciparum dihydrofolate reductase (DHFR). GOLD was used to dock 32 pyrimethamine derivatives into the active site of DHFR obtained from the x-ray crystal structure 1J3K.pdb. Several scoring functions were evaluated and the Molegro Protein-Ligand Interaction Score was determined to have one of the best correlation to experimental pK ( i ). In conjunction with Protein-Ligand Interaction scores, predicted binding modes and key protein-ligand interactions were evaluated and analyzed in order to develop criteria for selecting compounds having a greater chance of activity versus resistant strains of Plasmodium falciparum. This methodology will be used in future studies for selection of compounds for focused screening libraries.
authors: Natural Selection, Inc., 9330 Scranton Road, Suite 150, San Diego, CA 92121, USA.
authors: Gary B
authors: GB
authors: Fogel
authors: Mars
authors: M
authors: Cheung
authors: Eric
authors: E
authors: Pittman
authors: David
authors: D
authors: Hecht
mesh_terms: D000818:Animals; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D008958:Models, Molecular; D009154:Mutation; D010963:Plasmodium falciparum / Q000201:enzymology*; D011739:Pyrimethamine / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects* / Q000235:genetics
chemical_list: D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine