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Molecular Dynamics of Interactions between Rigid and Flexible Antifolates and Dihydrofolate Reductase from Pyrimethamine‐Sensitive and Pyrimethamine‐Resistant Plasmodium falciparum
Author(s) -
Mokmak Wanwimon,
Chunsrivirot Surasak,
Hangbua Supa,
Yuthavong Yongyuth,
Tongsima Sissades,
Kamchonwongpaisan Sumalee
Publication year - 2014
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12334
Subject(s) - dihydrofolate reductase , pyrimethamine , plasmodium falciparum , hydrogen bond , mutant , chemistry , antifolate , binding site , steric effects , stereochemistry , affinities , biology , biochemistry , enzyme , genetics , molecule , malaria , organic chemistry , antimetabolite , chemotherapy , gene , immunology
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 N 51I/ C 59 R / S 108 N / I 164 L mutations. The resistance was due to the steric conflict of PYR with S 108 N . WR 99210 ( 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 ( 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 .