PMID- 25829097
OWN - NLM
STAT- MEDLINE
DCOM- 20160425
LR  - 20150406
IS  - 1873-4243 (Electronic)
IS  - 1093-3263 (Linking)
VI  - 58
DP  - 2015 May
TI  - Molecular docking and molecular dynamics simulation studies of Trypanosoma cruzi 
      triosephosphate isomerase inhibitors. Insights into the inhibition mechanism and 
      selectivity.
PG  - 40-9
LID - S1093-3263(15)00036-4 [pii]
LID - 10.1016/j.jmgm.2015.02.002 [doi]
AB  - Trypanosoma cruzi (T. cruzi) triosephosphate isomerase (TcTIM) is a glycolytic 
      enzyme essential for parasite survival and has been considered an interesting 
      target for the development of new antichagasic compounds. The homodimeric enzyme 
      is catalytically active only as a dimer. Interestingly, significant differences 
      exist between the human and parasite TIMs interfaces with a sequence identity of 
      52%. Therefore, compounds able to specifically disrupt TcTIM but not Homo sapiens 
      TIM (hTIM) dimer interface could become selective antichagasic drugs. In the 
      present work, the binding modes of 1,2,4-thiadiazol, phenazine and 
      1,2,6-thiadiazine derivatives to TcTIM were investigated using molecular docking 
      combined with molecular dynamics (MD) simulations. The results show that 
      phenazine and 1,2,6-thiadiazine derivatives, 2 and 3, act as dimer-disrupting 
      inhibitors of TcTIM having also allosteric effects in the conformation of the 
      active site. On the other hand, the 1,2,4-thiadiazol derivative 1 binds into the 
      active site causing a significant decrease in enzyme mobility in both monomers. 
      The loss of conformational flexibility upon compound 1 binding suggests that this 
      inhibitor could be preventing essential motions of the enzyme required for 
      optimal activity. The lack of inhibitory activity of 1 against hTIM was also 
      investigated and seems to be related with the high mobility of hTIM which would 
      hinder the formation of a stable ligand-enzyme complex. This work has contributed 
      to understand the mechanism of action of this kind of inhibitors and could result 
      of great help for future rational novel drug design.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Minini, Lucia
AU  - Minini L
AD  - Laboratorio de Quimica Teorica y Computacional, Instituto de Quimica Biologica, 
      Facultad de Ciencias, Universidad de la Republica, Montevideo, Uruguay; Grupo de 
      Quimica Medicinal, Laboratorio de Quimica Organica, Facultad de Ciencias, 
      Universidad de la Republica, Montevideo, Uruguay.
FAU - Alvarez, Guzman
AU  - Alvarez G
AD  - Grupo de Quimica Medicinal, Laboratorio de Quimica Organica, Facultad de 
      Ciencias, Universidad de la Republica, Montevideo, Uruguay.
FAU - Gonzalez, Mercedes
AU  - Gonzalez M
AD  - Grupo de Quimica Medicinal, Laboratorio de Quimica Organica, Facultad de 
      Ciencias, Universidad de la Republica, Montevideo, Uruguay.
FAU - Cerecetto, Hugo
AU  - Cerecetto H
AD  - Grupo de Quimica Medicinal, Laboratorio de Quimica Organica, Facultad de 
      Ciencias, Universidad de la Republica, Montevideo, Uruguay; Area de 
      Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, 
      Universidad de la Republica, Montevideo, Uruguay.
FAU - Merlino, Alicia
AU  - Merlino A
AD  - Laboratorio de Quimica Teorica y Computacional, Instituto de Quimica Biologica, 
      Facultad de Ciencias, Universidad de la Republica, Montevideo, Uruguay. 
      Electronic address: amerlino@fcien.edu.uy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150221
PL  - United States
TA  - J Mol Graph Model
JT  - Journal of molecular graphics & modelling
JID - 9716237
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Phenazines)
RN  - 0 (Thiadiazines)
RN  - 0 (Thiadiazoles)
RN  - 0 (phenazine)
RN  - EC 5.3.1.1 (Triose-Phosphate Isomerase)
SB  - IM
MH  - Catalytic Domain
MH  - Drug Design
MH  - Enzyme Inhibitors/*chemistry/*metabolism/pharmacology
MH  - Molecular Docking Simulation
MH  - Molecular Dynamics Simulation
MH  - Phenazines/chemistry/metabolism
MH  - Thiadiazines/chemistry/metabolism
MH  - Thiadiazoles/chemistry/metabolism
MH  - Triose-Phosphate Isomerase/*antagonists & inhibitors/chemistry/metabolism
MH  - Trypanosoma cruzi/*enzymology
OTO - NOTNLM
OT  - Dimer-disrupting inhibitors
OT  - Molecular docking
OT  - Molecular dynamics
OT  - Rational drug design
OT  - Selective TcTIM inhibitors
EDAT- 2015/04/02 06:00
MHDA- 2016/04/26 06:00
CRDT- 2015/04/02 06:00
PHST- 2014/05/25 00:00 [received]
PHST- 2014/11/22 00:00 [revised]
PHST- 2015/02/12 00:00 [accepted]
PHST- 2015/04/02 06:00 [entrez]
PHST- 2015/04/02 06:00 [pubmed]
PHST- 2016/04/26 06:00 [medline]
AID - S1093-3263(15)00036-4 [pii]
AID - 10.1016/j.jmgm.2015.02.002 [doi]
PST - ppublish
SO  - J Mol Graph Model. 2015 May;58:40-9. doi: 10.1016/j.jmgm.2015.02.002. Epub 2015 
      Feb 21.