Open AccessBiomolecular study of human thymidylate synthase conformer-selective inhibitors: New chemotherapeutic approach
Author(s) -
Hala O. ElMesallamy,
Hekmat M. El Magdoub,
James Chapman,
Nadia M. Hamdy,
Mona F. Schaalan,
Lamiaa N. Hammad,
Sondra H. Berger
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0193810
Subject(s) - thymidylate synthase , conformational isomerism , chemistry , selectivity , enzyme , stereochemistry , raltitrexed , biochemistry , active site , combinatorial chemistry , biophysics , biology , molecule , organic chemistry , cancer , fluorouracil , genetics , catalysis
Thymidylate synthase (TS) is a well-validated target for the therapy of adult cancers. Propane-1,3-diphosphonic acid (PDPA) has significant inhibitory properties against human thymidylate synthase (hTS) relative to mouse TS which is not predicted to adopt an inactive conformer. The current research aims to identify novel, lead inhibitors of hTS and examine the prediction that they bind selectively to hTS enzymes existing in different conformational equilibria. Conformer-selectivity was evaluated through performing activity inhibition studies, as well as intrinsic fluorescence (IF) studies in comparison to the known orthosteric inhibitor raltitrexed (RTX). Human TS was isolated from recombinant bacteria expressing either native hTS, capable of conformational switching, or an actively stabilized mutant (R163K-hTS). The examined test compounds were rationally or virtually predicted to have inhibitory activity against hTS. Among these compounds, glutarate, N-(4-carboxyphenyl) succinamic acid, and diglycolic anhydride showed higher selectivity towards native hTS as compared to R163K-hTS. The active site inhibitor RTX showed significantly higher inhibition of R163K-hTS relative to hTS. Targeting hTS via conformational selectivity represents a future approach for overcoming reported resistance towards active-state TS analogs.