Crystal structure of dihydrofolate reductase from the filarial nematode W. bancrofti in complex with NADPH and folate.

Autor: Lange K; Department of Chemistry and Biochemistry, Montclair State University, Montclair, New Jersey, United States of America., Frey KM; School of Pharmacy and Health Sciences, Fairleigh Dickinson University, Florham Park, New Jersey, United States of America., Eck T; Department of Chemistry and Biochemistry, Montclair State University, Montclair, New Jersey, United States of America., Janson CA; Department of Chemistry and Biochemistry, Montclair State University, Montclair, New Jersey, United States of America., Gubler U; Department of Chemistry and Biochemistry, Montclair State University, Montclair, New Jersey, United States of America., Goodey NM; Department of Chemistry and Biochemistry, Montclair State University, Montclair, New Jersey, United States of America.
Jazyk: angličtina
Zdroj: PLoS neglected tropical diseases [PLoS Negl Trop Dis] 2023 Apr 27; Vol. 17 (4), pp. e0011303. Date of Electronic Publication: 2023 Apr 27 (Print Publication: 2023).
DOI: 10.1371/journal.pntd.0011303
Abstrakt: Lymphatic filariasis is a debilitating illness with an estimated 50 million cases as of 2018. The majority of cases are caused by the parasitic worm W. bancrofti and additional cases by the worms B. malayi and B. timori. Dihydrofolate reductase (DHFR) is an established target in the treatment of cancer, bacterial, and protozoal infections and may be a potential target for drugs targeting parasitic worm infections, including filariasis. Recent studies have shown that known antifolate compounds, including methotrexate, inhibit the activity of W. bancrofti DHFR (WbDHFR). However, the absence of structural information for filarial DHFRs has limited the study of more in-depth structure-function relationships. We report the structure of WbDHFR complexed with NADPH and folate using X-ray diffraction data measured to 2.47 Å resolution. The structure of WbDHFR reveals the usual DHFR fold and is currently only the second nematode DHFR structure in the Protein Data Bank. The equilibrium dissociation constants for NADPH (90 ± 29 nM) and folate (23 ± 4 nM) were determined by equilibrium titrations. The interactions of known antifolates with WbDHFR were analyzed using molecular docking programs and molecular dynamics simulations. Antifolates with a hydrophobic core and extended linker formed favorable interactions with WbDHFR. These combined data should now facilitate the rational design of filarial DHFR inhibitors, which in turn can be used to determine whether DHFR is a viable drug target for filariasis and whether existing antifolates may be repurposed for its treatment.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Lange et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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