@article{BajdaWieckowskaHebdaetal.2013,
  author    = {Bajda, Marek and Wieckowska, Anna and Hebda, Michalina and Guzior, Natalia and Sotriffer, Christoph A. and Malawska, Barbara},
  title     = {Structure-Based Search for New Inhibitors of Cholinesterases},
  series = {International Journal of Molecular Sciences},
  volume    = {14},
  journal   = {International Journal of Molecular Sciences},
  number    = {3},
  doi       = {10.3390/ijms14035608},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129423},
  pages     = {5608-5632},
  year      = {2013},
  abstract  = {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.},
  language  = {en}
}
@article{DaryaeeChangSchiebeletal.2016,
  author    = {Daryaee, Fereidoon and Chang, Andrew and Schiebel, Johannes and Lu, Yang and Zhang, Zhuo and Kapilashrami, Kanishk and Walker, Stephen G. and Kisker, Caroline and Sotriffer, Christoph A. and Fisher, Stewart L. and Tonge, Peter J.},
  title     = {Correlating drug-target kinetics and in vivo pharmacodynamics: long residence time inhibitors of the FabI enoyl-ACP reductase},
  series = {Chemical Science},
  volume    = {7},
  journal   = {Chemical Science},
  number    = {9},
  doi       = {10.1039/c6sc01000h},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191218},
  pages     = {5945-5954},
  year      = {2016},
  abstract  = {Drug-target kinetics enable time-dependent changes in target engagement to be quantified as a function of drug concentration. When coupled to drug pharmacokinetics (PK), drug-target kinetics can thus be used to predict in vivo pharmacodynamics (PD). Previously we described a mechanistic PK/PD model that successfully predicted the antibacterial activity of an LpxC inhibitor in a model of Pseudomonas aeruginosa infection. In the present work we demonstrate that the same approach can be used to predict the in vivo activity of an enoyl-ACP reductase (FabI) inhibitor in a model of methicillin-resistant Staphylococcus aureus (MRSA) infection. This is significant because the LpxC inhibitors are cidal, whereas the FabI inhibitors are static. In addition P. aeruginosa is a Gram-negative organism whereas MRSA is Gram-positive. Thus this study supports the general applicability of our modeling approach across antibacterial space.},
  language  = {en}
}
@article{KochCappelNockeretal.2013,
  author    = {Koch, Oliver and Cappel, Daniel and Nocker, Monika and J{\"a}ger, Timo and Floh{\´e}, Leopold and Sotriffer, Christoph A. and Selzer, Paul M.},
  title     = {Molecular Dynamics Reveal Binding Mode of Glutathionylspermidine by Trypanothione Synthetase},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {2},
  doi       = {10.1371/journal.pone.0056788},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131070},
  pages     = {e56788},
  year      = {2013},
  abstract  = {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.},
  language  = {en}
}
@article{MergetSotriffer2015,
  author    = {Merget, Benjamin and Sotriffer, Christoph A.},
  title     = {Slow-Onset Inhibition of Mycobacterium tuberculosis InhA: Revealing Molecular Determinants of Residence Time by MD Simulations},
  series = {PLoS One},
  volume    = {10},
  journal   = {PLoS One},
  number    = {5},
  doi       = {10.1371/journal.pone.0127009},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125607},
  pages     = {e0127009},
  year      = {2015},
  abstract  = {An important kinetic parameter for drug efficacy is the residence time of a compound at a drug target, which is related to the dissociation rate constant koff. For the essential antimycobacterial target InhA, this parameter is most likely governed by the ordering of the flexible substrate binding loop (SBL). Whereas the diphenyl ether inhibitors 6PP and triclosan (TCL) do not show loop ordering and thus, no slow-binding inhibition and high koff values, the slightly modified PT70 leads to an ordered loop and a residence time of 24 minutes. To assess the structural differences of the complexes from a dynamic point of view, molecular dynamics (MD) simulations with a total sampling time of 3.0 µs were performed for three ligand-bound and two ligand-free (perturbed) InhA systems. The individual simulations show comparable conformational features with respect to both the binding pocket and the SBL, allowing to define five recurring conformational families. Based on their different occurrence frequencies in the simulated systems, the conformational preferences could be linked to structural differences of the respective ligands to reveal important determinants of residence time. The most abundant conformation besides the stable EI* state is characterized by a shift of Ile202 and Val203 toward the hydrophobic pocket of InhA. The analyses revealed potential directions for avoiding this conformational change and, thus, hindering rapid dissociation: (1) an anchor group in 2'-position of the B-ring for scaffold stabilization, (2) proper occupation of the hydrophobic pocket, and (3) the introduction of a barricade substituent in 5'-position of the diphenyl ether B-ring.},
  language  = {en}
}