In silico screening against wild-type and mutant Plasmodium falciparum dihydrofolate reductase.
Modeling studies were performed on known inhibitors of wild-type as well as quadruple mutant Plasmodium falciparum dihydrofolate reductase (DHFR). GOLD was used to dock 31 pyrimethamine derivatives into the active site of DHFR obtained from the X-ray crystal structures 1J3I.pdb and 1J3K.pdb. Predicted binding affinities from a scoring function were analyzed and evaluated in order to develop criteria for selecting compounds having a greater chance of activity versus wild-type and resistant strains of P. falciparum for future high-throughput screening experiments.
Natural Selection Inc., 9330 Scranton Road, Suite 150, San Diego, CA 92121, USA.
Gary B
GB
Fogel
Mars
M
Cheung
Eric
E
Pittman
David
D
Hecht
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D017076:Computer-Aided Design; D015195:Drug Design; D004351:Drug Resistance / Q000235:genetics; D005493:Folic Acid Antagonists / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011739:Pyrimethamine / Q000737:chemistry* / Q000494:pharmacology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D000962:Antimalarials; D005493:Folic Acid Antagonists; D008024:Ligands; D015800:Protozoan Proteins; D054852:Small Molecule Libraries; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine