PMID- 29538414
OWN - NLM
STAT- MEDLINE
DCOM- 20180628
LR  - 20181114
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 13
IP  - 3
DP  - 2018
TI  - Biomolecular study of human thymidylate synthase conformer-selective inhibitors: 
      New chemotherapeutic approach.
PG  - e0193810
LID - 10.1371/journal.pone.0193810 [doi]
LID - e0193810
AB  - 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.
FAU - El-Mesallamy, Hala O
AU  - El-Mesallamy HO
AUID- ORCID: 0000-0001-8190-536X
AD  - Department of Biochemistry, Faculty of Pharmacy, Ain Sham University, Cairo, 
      Egypt.
FAU - El Magdoub, Hekmat M
AU  - El Magdoub HM
AD  - Department of Biochemistry, Faculty of Pharmacy, Misr International University, 
      Cairo, Egypt.
FAU - Chapman, James M
AU  - Chapman JM
AD  - Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, 
      University of South Carolina, Columbia, SC, United States of America.
FAU - Hamdy, Nadia M
AU  - Hamdy NM
AD  - Department of Biochemistry, Faculty of Pharmacy, Ain Sham University, Cairo, 
      Egypt.
FAU - Schaalan, Mona F
AU  - Schaalan MF
AD  - Department of Biochemistry, Faculty of Pharmacy, Misr International University, 
      Cairo, Egypt.
FAU - Hammad, Lamiaa N
AU  - Hammad LN
AD  - Department of Biochemistry, Faculty of Pharmacy, Misr International University, 
      Cairo, Egypt.
FAU - Berger, Sondra H
AU  - Berger SH
AD  - Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, 
      University of South Carolina, Columbia, SC, United States of America.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180314
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Pregnadienes)
RN  - 0 (Quinazolines)
RN  - 0 (Thiophenes)
RN  - 0 (pregna-1,4-dien-3-on-20-al)
RN  - EC 2.1.1.45 (Thymidylate Synthase)
RN  - FCB9EGG971 (raltitrexed)
SB  - IM
MH  - Antineoplastic Agents/chemistry/*pharmacology
MH  - Catalytic Domain/drug effects/genetics
MH  - Dose-Response Relationship, Drug
MH  - Drug Discovery
MH  - Enzyme Inhibitors/chemistry/*pharmacology
MH  - Escherichia coli
MH  - Humans
MH  - Molecular Docking Simulation
MH  - Mutation
MH  - Pregnadienes/chemistry/pharmacology
MH  - Protein Conformation/drug effects
MH  - Quinazolines/chemistry/pharmacology
MH  - Thiophenes/chemistry/pharmacology
MH  - Thymidylate Synthase/*antagonists & inhibitors/genetics/metabolism
PMC - PMC5851609
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2018/03/15 06:00
MHDA- 2018/06/29 06:00
PMCR- 2018/03/14
CRDT- 2018/03/15 06:00
PHST- 2017/05/02 00:00 [received]
PHST- 2018/02/19 00:00 [accepted]
PHST- 2018/03/15 06:00 [entrez]
PHST- 2018/03/15 06:00 [pubmed]
PHST- 2018/06/29 06:00 [medline]
PHST- 2018/03/14 00:00 [pmc-release]
AID - PONE-D-17-16817 [pii]
AID - 10.1371/journal.pone.0193810 [doi]
PST - epublish
SO  - PLoS One. 2018 Mar 14;13(3):e0193810. doi: 10.1371/journal.pone.0193810. 
      eCollection 2018.