We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Molecular Dynamics of Interactions between Rigid and Flexible Antifolates and Dihydrofolate Reductase from Pyrimethamine-Sensitive and Pyrimethamine-Resistant Plasmodium falciparum.
- Authors
Mokmak, Wanwimon; Chunsrivirot, Surasak; Hannongbua, Supa; Yuthavong, Yongyuth; Tongsima, Sissades; Kamchonwongpaisan, Sumalee
- Abstract
Currently, the usefulness of antimalarials such as pyrimethamine ( PYR) is drastically reduced due to the emergence of resistant Plasmodium falciparum ( Pf) caused by its dihydrofolate reductase ( Pf DHFR) mutations, especially the quadruple N51I/ C59 R/ S108 N/ I164 L mutations. The resistance was due to the steric conflict of PYR with S108 N. WR99210 ( WR), a dihydrotriazine antifolate with a flexible side chain that can avoid such conflict, can overcome this resistance through tight binding with the mutant. To understand factors contributing to different binding affinities of PYR/ WR to the wild type ( WT) and quadruple mutant ( QM), we performed simulations on WR- WT, WR- QM, PYR- WT, and PYR- QM complexes and found that Ile14 and Asp54 were crucial for PYR/ WR binding to Pf DHFR due to strong hydrogen bonds. The quadruple mutations cause PYR to form, on average, fewer hydrogen bonds with Ile14 and Leu164, and to be displaced from its optimal orientation for Asp54 interaction. The predicted binding affinity ranking ( WR- QM ≈ WR- WT ≈ PYR- WT >> PYR- QM) reasonably agrees with the inhibition constant ( Ki) ranking. Our results reveal important residues for tight binding of PYR/ WR to WT/ QM, which may be used to evaluate the inhibition effectiveness of antimalarials and to provide fundamental information for designing new drugs effective against drug-resistant P. falciparum.
- Subjects
TETRAHYDROFOLATE dehydrogenase; ANTIMALARIALS; PLASMODIUM falciparum; MOLECULAR dynamics; HYDROGEN bonding; DRUG resistance
- Publication
Chemical Biology & Drug Design, 2014, Vol 84, Issue 4, p450
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.12334