title: Interactions between cycloguanil derivatives and wild type and resistance-associated mutant Plasmodium falciparum dihydrofolate reductases.
abstract: Comparative molecular field analysis (CoMFA) and quantum chemical calculations were performed on cycloguanil (Cyc) derivatives of the wild type and the quadruple mutant (Asn51Ile, Cys59Arg, Ser108Asn, Ile164Leu) of Plasmodium falciparum dihydrofolate reductase (PfDHFR). The represented CoMFA models of wild type (r(2) = 0.727 and r(2) = 0.985) and mutant type (r(2) = 0.786 and r(2) = 0.979) can describe the differences of the Cyc structural requirements for the two types of PfDHFR enzymes and can be useful to guide the design of new inhibitors. Moreover, the obtained particular interaction energies between the Cyc and the surrounding residues in the binding pocket indicated that Asn108 of mutant enzyme was the cause of Cyc resistance by producing steric clash with p-Cl of Cyc. Consequently, comparing the energy contributions with the potent flexible WR99210 inhibitor, it was found that the key mutant residue, Asn108, demonstrates attractive interaction with this inhibitor and some residues, Leu46, Ile112, Pro113, Phe116, and Leu119, seem to perform as second binding site with WR99210. Therefore, quantum chemical calculations can be useful for investigating residue interactions to clarify the cause of drug resistance.
authors.affiliation: Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
authors.forename: Phornphimon
authors.initials: P
authors.lastname: Maitarad
authors.forename: Sumalee
authors.initials: S
authors.lastname: Kamchonwongpaisan
authors.forename: Jarunee
authors.initials: J
authors.lastname: Vanichtanankul
authors.forename: Tirayut
authors.initials: T
authors.lastname: Vilaivan
authors.forename: Yongyuth
authors.initials: Y
authors.lastname: Yuthavong
authors.forename: Supa
authors.initials: S
authors.lastname: Hannongbua
mesh_terms: D000465:Algorithms; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain / Q000235:genetics; D015195:Drug Design; D004351:Drug Resistance / Q000235:genetics*; D005493:Folic Acid Antagonists / Q000737:chemistry; D006860:Hydrogen Bonding; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics; D002727:Proguanil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D011789:Quantum Theory; D055672:Static Electricity; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D013816:Thermodynamics; D014227:Triazines / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000962:Antimalarials; D005493:Folic Acid Antagonists; D014227:Triazines; C026009:cycloguanil; D013762:Tetrahydrofolate Dehydrogenase; D002727:Proguanil