title: Targeting folate metabolism for therapeutic option: A bioinformatics approach.
abstract: Lymphatic filariasis, commonly called elephantiasis, poses a burden of estimated level of 5.09 million disability adjusted life year. Limitations of its sole drug, diethylcarbamazine (DEC) drive exploration of effective filarial target. A few plant extracts having polyphenolic ingredients and some synthetic compounds possess potential dihydrofolate reductase (DHFR) inhibitory effect. Here, we postulated a plausible link between folates and polyphenolics based on their common precursor in shikimate metabolism. Considering its implication in structural resemblance based antagonism, we have attempted to validate parasitic DHFR protein as a target. The bioinformatics approach, in the absence of crystal structure of the proposed target, used to authenticate and for virtual docking with suitable tested compounds, showed remarkably lower thermodynamic parameters as opposed to the positive control. A comparative docking analysis between human and Brugia malayi DHFR also showed effective binding parameters with lower inhibition constants of these ligands with parasitic target, but not with human counterpart highlighting safety and efficacy. This study suggests that DHFR could be a valid drug target for lymphatic filariasis, and further reveal that bioinformatics may be an effective tool in reverse pharmacological approach for drug design.
authors.forename: Sneha
authors.initials: S
authors.lastname: Hande
authors.forename: Kalyan
authors.initials: K
authors.lastname: Goswami
authors.forename: Richa
authors.initials: R
authors.lastname: Sharma
authors.forename: Priyanka
authors.initials: P
authors.lastname: Bhoj
authors.forename: Lingaraj
authors.initials: L
authors.lastname: Jena
authors.forename: Maryada Venkata Rami
authors.initials: MV
authors.lastname: Reddy
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000627:therapeutic use; D017178:Brugia malayi / Q000201:enzymology; D019295:Computational Biology; D005368:Filariasis / Q000188:drug therapy / Q000469:parasitology; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects / Q000378:metabolism
chemical_list: D000871:Anthelmintics; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase