{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T01:29:50Z","timestamp":1788571790383,"version":"build-2803163510"},"reference-count":58,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2014,6,4]],"date-time":"2014-06-04T00:00:00Z","timestamp":1401840000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2014,10]]},"abstract":"Currently, the usefulness of antimalarials such as pyrimethamine (PYR<\/jats:styled-content>) is drastically reduced due to the emergence of resistant Plasmodium falciparum<\/jats:italic> (Pf<\/jats:italic>) caused by its dihydrofolate reductase (Pf<\/jats:italic>DHFR<\/jats:styled-content>) mutations, especially the quadruple N<\/jats:styled-content>51I\/C<\/jats:styled-content>59R<\/jats:styled-content>\/S<\/jats:styled-content>108N<\/jats:styled-content>\/I<\/jats:styled-content>164L<\/jats:styled-content> mutations. The resistance was due to the steric conflict of PYR<\/jats:styled-content> with S<\/jats:styled-content>108N<\/jats:styled-content>. WR<\/jats:styled-content>99210 (WR<\/jats:styled-content>), 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<\/jats:styled-content>\/WR<\/jats:styled-content> to the wild type (WT<\/jats:styled-content>) and quadruple mutant (QM<\/jats:styled-content>), we performed simulations on WR<\/jats:styled-content>\u2010WT<\/jats:styled-content>, WR<\/jats:styled-content>\u2010QM<\/jats:styled-content>, PYR<\/jats:styled-content>\u2010WT<\/jats:styled-content>, and PYR<\/jats:styled-content>\u2010QM<\/jats:styled-content> complexes and found that Ile14 and Asp54 were crucial for PYR<\/jats:styled-content>\/WR<\/jats:styled-content> binding to Pf<\/jats:italic>DHFR<\/jats:styled-content> due to strong hydrogen bonds. The quadruple mutations cause PYR<\/jats:styled-content> 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<\/jats:styled-content>\u2010QM<\/jats:styled-content>\u00a0\u2248\u00a0WR<\/jats:styled-content>\u2010WT<\/jats:styled-content>\u00a0\u2248\u00a0PYR<\/jats:styled-content>\u2010WT<\/jats:styled-content>\u00a0>>\u00a0PYR<\/jats:styled-content>\u2010QM<\/jats:styled-content>) reasonably agrees with the inhibition constant (K<\/jats:italic>i<\/jats:sub>) ranking. Our results reveal important residues for tight binding of PYR<\/jats:styled-content>\/WR<\/jats:styled-content> to WT<\/jats:styled-content>\/QM<\/jats:styled-content>, which may be used to evaluate the inhibition effectiveness of antimalarials and to provide fundamental information for designing new drugs effective against drug\u2010resistant P<\/jats:italic>.\u00a0falciparum<\/jats:italic>.<\/jats:p>","DOI":"10.1111\/cbdd.12334","type":"journal-article","created":{"date-parts":[[2014,4,9]],"date-time":"2014-04-09T13:47:15Z","timestamp":1397051235000},"page":"450-461","source":"Crossref","is-referenced-by-count":38,"title":["Molecular Dynamics of Interactions between Rigid and Flexible Antifolates and Dihydrofolate Reductase from Pyrimethamine\u2010Sensitive and Pyrimethamine\u2010Resistant Plasmodium falciparum<\/i>"],"prefix":"10.1111","volume":"84","author":[{"given":"Wanwimon","family":"Mokmak","sequence":"first","affiliation":[{"name":"National Center for Genetic Engineering and 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