TY  - JOUR
A1  - Koch, Oliver
A1  - Cappel, Daniel
A1  - Nocker, Monika
A1  - Jäger, Timo
A1  - Flohé, Leopold
A1  - Sotriffer, Christoph A.
A1  - Selzer, Paul M.
T1  - Molecular Dynamics Reveal Binding Mode of Glutathionylspermidine by Trypanothione Synthetase
JF  - PLoS ONE
N2  - The trypanothione synthetase (TryS) catalyses the two-step biosynthesis of trypanothione from spermidine and glutathione and is an attractive new drug target for the development of trypanocidal and antileishmanial drugs, especially since the structural information of TryS from Leishmania major has become available. Unfortunately, the TryS structure was solved without any of the substrates and lacks loop regions that are mechanistically important. This contribution describes docking and molecular dynamics simulations that led to further insights into trypanothione biosynthesis and, in particular, explains the binding modes of substrates for the second catalytic step. The structural model essentially confirm previously proposed binding sites for glutathione, ATP and two \(Mg^{2+}\) ions, which appear identical for both catalytic steps. The analysis of an unsolved loop region near the proposed spermidine binding site revealed a new pocket that was demonstrated to bind glutathionylspermidine in an inverted orientation. For the second step of trypanothione synthesis glutathionylspermidine is bound in a way that preferentially allows \(N^1\)-glutathionylation of \(N^8\)-glutathionylspermidine, classifying \(N^8\)-glutathionylspermidine as the favoured substrate. By inhibitor docking, the binding site for \(N^8\)-glutathionylspermidine was characterised as druggable.
KW  - purification
KW  - crithidia fasciulata
KW  - trypanosoma cruzi
KW  - RESP model
KW  - biosynthesis
KW  - chemotherapy
KW  - metabolism
KW  - brucei
KW  - system
KW  - leishmaniasis
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131070
VL  - 8
IS  - 2
ER  - 
TY  - JOUR
A1  - Bajda, Marek
A1  - Wieckowska, Anna
A1  - Hebda, Michalina
A1  - Guzior, Natalia
A1  - Sotriffer, Christoph A.
A1  - Malawska, Barbara
T1  - Structure-Based Search for New Inhibitors of Cholinesterases
JF  - International Journal of Molecular Sciences
N2  - Cholinesterases are important biological targets responsible for regulation of cholinergic transmission, and their inhibitors are used for the treatment of Alzheimer’s disease. To design new cholinesterase inhibitors, of different structure-based design strategies was followed, including the modification of compounds from a previously developed library and a fragment-based design approach. This led to the selection of heterodimeric structures as potential inhibitors. Synthesis and biological evaluation of selected candidates confirmed that the designed compounds were acetylcholinesterase inhibitors with \(IC_{50}\) values in the mid-nanomolar to low micromolar range, and some of them were also butyrylcholinesterase inhibitors.
KW  - fragment-based design
KW  - cholinesterases inhibitors
KW  - butyrylcholinesterase
KW  - acetylcholinesterase
KW  - drug design
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129423
VL  - 14
IS  - 3
ER  -