Molecular dynamics of interactions between rigid and flexible antifolates and dihydrofolate reductase from pyrimethamine-sensitive and pyrimethamine-resistant Plasmodium falciparum.
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 (PfDHFR) mutations, especially the quadruple N51I/C59R/S108N/I164L mutations. The resistance was due to the steric conflict of PYR with S108N. 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 PfDHFR 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 (K(i)) 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.
National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, 113 Thailand Science Park, Phahonyothin Road, Khlong Nueng, Klong Luang, Pathum Thani, 12120, Thailand.
Wanwimon
W
Mokmak
Surasak
S
Chunsrivirot
Supa
S
Hannongbua
Yongyuth
Y
Yuthavong
Sissades
S
Tongsima
Sumalee
S
Kamchonwongpaisan
D001665:Binding Sites; D004351:Drug Resistance; D005493:Folic Acid Antagonists / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009249:NADP / Q000737:chemistry / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D017434:Protein Structure, Tertiary; D011739:Pyrimethamine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics
D005493:Folic Acid Antagonists; D009249:NADP; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine
MM-PBSA; Pf
DHFR; WR99210; antimalarials; molecular dynamics simulations; pyrimethamine