Molecular Design

Computational Drug Design

This project pursuits the development of molecules with specific properties. Therefore, methods are developed, which make the simulation of large molecular systems such as receptor-ligand-complexes possible. The focus lies on simulation of binding processes and estimation of binding affinities. Current highlights are our methods for reconstruction of a binding path of the ligand into the receptor and simulation inside the binding pocket. Using conformation dynamics together with PCCA+, we have designed a new generalized transfer operator for the simulation of molecular kinetics, which allows one to compute the transition rate matrix without running long molecular dynamics simulations. Our actual applications are development of pain relief drugs with restricted field of action and exploration of the toxicity of flame retardants.

Methods, algorithms and software

For simulation of binding processes, we have extended the conformation dynamics approach. A conformation of a ligand-receptor-complex is described now by the conformation of the ligand, the conformation of the receptor and linear distances between ligand and receptor atoms. Using this definition, we have developed methods for reconstruction of a binding path of the ligand into the receptor (Bujotzek, Weber 2009; Durmaz 2009) and simulation inside the binding pocket (Weber 2009, Scharkoi 2009). Further, we have proven that by using conformation dynamics together with PCCA+, it is possible to design a new generalized transfer operator for the simulation of molecular kinetics, which allows one to compute the transition rate matrix without running long molecular dynamics simulations (Weber 2009). Using these new theoretical results, we hope to develop more efficient algorithms for simulation of molecules.

Applications

Design of pain relief drugs

The goal of this project is design of pain relief drugs (opioids), which should be active only in inflamed tissue and therefore have reduced side effects compared to conventional opioids. We managed to develop a candidate (Scharkoi, 2009), which was synthesized by the ASCA GmbH in Berlin. The opioid is currently undergoing in-vivo and in-vitro experiments at the Charité Berlin.

Exploration of the toxicity of flame retardants

In this project we studied the binding behavior of the flame retardant HBCD and its degradation products to the human thyroid receptor (hTTR). We compared the results of the binding studies of HBCD, PBCD and BDE to these of thyroxine, a natural ligand of hTTR. We identified two PBCD isomers which seem to have higher affinity to hTTR as thyroxine itself (Durmaz, 2009). Hence, these two PBCD candidates are strongly recommended to be paid more attention to under the EU risk assessment.

Publications

• R.  Kellermann, M.  Weber, A.  Bujotzek
  Vom Dietrich zum Sicherheitsschlüssel – Mathematiker des Matheon simulieren neuen Wirkstoff für die Diabetes-Behandlung
   (2) DFG-Forschungszentrum Matheon  Newsletter (Herbst 2007)
• M. Weber, V. Durmaz, R. Becker
  Predictive Identification of Pentabromocyclododecane (PBCD) Isomers with high Binding Affinity to hTTR
   -accepted for publication (2009)
• A. Bujotzek, M. Weber
  Efficient Simulation of Ligand-Receptor Binding Processes Using the Conformation Dynamics Approach
  Journal of Bioinformatics and Computational Biology,  Vol. 7(5),   811-831 (2009)
• M. Weber
  A Subspace Approach to Molecular Markov State Models via an Infinitesimal Generator
  Zuse Institute, Berlin  -preparations for a post-doctoral thesis (2009)
• V. Durmaz
  Theoretical Investigations on HBCD and PBCD: Interconversion Rates and Receptor Binding Processes
  Freie Universität Berlin (2009)
• D. Siegel, K. Andrae, M. Proske, C. Kochan, M. Koch, M. Weber, I. Nehls
  Dynamic covalent hydrazine chemistry as a specific extraction and cleanup technique for the quantification of the Fusarium mycotoxin zearalenone in edible oils
   -accepted for publication (2009)
• R. Köppen, R. Becker, M. Weber, V. Durmaz, I. Nehls
  HBCD stereoisimers: Thermal interconversion and enantiospecific trace analysis in biota
  Organohalogen Compounds,  Vol. 70,   910-913 (2009)
• M. Weber
  Spurenstoffe im Trinkwasser - Risikoqualifizierung im Rechner?
  In: Schriftenreihe des Vereins für Wasser-, Boden- und Lufthygiene,  L. Dunemann and O. Schmoll  (ed)  -CD-ROM (2009)
• O. Scharkoi
  Conformation Dynamics Design of Pain Relief Drugs
  Freie Universität Berlin (2009)
• C. Förster, A. B. E. Brauer, J. P. Fürste, C. Betzel, M. Weber, F. Cordes, V. A. Erdmann
  Visualization of the tRNA(Ser) acceptor step binding site in the seryl-tRNA synthetase
  BBRC,  Vol. 362  (2) ,   415–418 (2007)
• D.  Baum
  A Point-Based Algorithm for Multiple 3D Surface Alignment of Drug-Sized Molecules
  Freie Universität Berlin  Dissertation (2007)
• A. Gürler, S. Moll, M. Weber, H. Meyer, F. Cordes
  Selection and flexible optimization of binding modes from conformation ensembles
  Biosystems (2007)
• O.  Scharkoi
  Simulation von Opioiden in Abhängigkeit von Temperatur und pH-Wert
  Freie Universität Berlin, Bioinformatik  Bachelorarbeit (2007)

Organizational Details

Members

Peter Deuflhard
Alexander Bujotzek
Konstantin Fackeldey
Karsten Andrae
Olga Scharkoi
Vedat Durmaz
Ole Schütt
Martina Klimm

Responsible

Peter Deuflhard
Marcus Weber

Partners

Christoph Stein (Charité Berlin)
Roland Becker (BAM: Federal Institute for Materials Research and Testing)
Jörg Rademann (FMP: Leibniz-Institute for Molecular Pharmocology)
Hua Fan (Charité Berlin)

Funding

DFG Research Center MATHEON "Mathematics for key technologies",Research Project A4 BAM Bundesanstalt für Materialforschung

Duration

07/2006 -