Medikamentenentwicklung durch Rezeptor-Ligand-Docking
Final Report Abstract
With the completion of this project we could show that a biophysics-based simulation approach can be competitive with more established knowledge-based in-silico screening techniques, including the successful fragment-based methods. Rigid-receptor screens with FlexScreen predict binding modes wilh at least the same accuracy as the best competing techniques presently available. Flexible receptor models (at the level of sidechain flexibility) improve not only docking rates and poses of known ligands, but even enrichment rates in screening experiments against large databases. These results establish our approach at the interface between high accuracy, but very costly molecular-mechanics based simulation methods for relative/absolute ligand-receptor affinity calculations on one hand and traditional, fast, high-throughput screening techniques on the other. They also clearly point to the direction in which we should develop our method further: better implicit solvent models, which are loo expensive in traditional implementations to be directly incorporated into screening methods, need lo be developed to improve affinity estimates. In the course ofthis work we have already experimented with several methods, but to date not succeeded to find a truly viable compromise between accuracy and computational speed (evaluation of the solvent term at every step in the docking procedure). Given the success of the flexible-sidechain model, an obvious direction for further improvement is the incorporafion of local backbone flexibility into the docking protocol. We believe that sampling ofthe protein degrees of freedom during the simulation will permit the treatment of larger class of problems in comparison to ensemble docking. However, such an approach is computationally expensive and requires an accurate scoring function that treats protein-protein and protein-ligand interactions on the same footing. Realization of such an approach would permit the treatment of many induced-fit problems that are known to be relevant for important pharmaceutical targets, such as the DFG-loop in kinases. Due to its biophysical, forcefield-based interaction model and efficient sampling techniques, our method is well suited to make the next step in this direction.
Publications
- High Throughput in-silico screening against flexible protein receptors. Modern Methods for Theoretical Chemical Physics of Biopolymers, 179-89 (2005)
B. Fischer, H. Merlitz, and W. Wenzel
- High throughput in-silico screening with target flexibility using FlexScreen. Accelrys European Science Forum 2006, Heidelberg, November 28, 2006
Wenzel, W.
- High throughput in-silico screening with target flexibility. Deutsches Krebsforschungszentrum, Heidelberg, 9.Februar 2006
Wenzel, W.
- High troughput in-silico screening against flexible protein receptors. Sanofi-Aventis AG, Frankfurt, 1.Februar 2006
Fischer, B.; Merlitz, H.; Wenzel, W.
- Accuracy of binding mode prediction with a cascadic stochastic tunneling method. Proteins, Structure, Function and Bioinformatics 68, 196 (2007)
B. Fischer, S. Basili, H. Merlitz, and W. Wenzel
- Analysis and Optimization of the Flex-Screen Docking Approach Using DUD Benchmarking Database in U.H.E. Hansmann, J. Meinke, S. Mohanty (eds.): From Computational Biophysics to Systems Biology, NIC Series 38, pp. 181-192 (2007)
D. Kokh, B. Fischer and W.Wenzel
- Crystal Water Molecules and Solvation Effects on Protein-Ligand Docking in U.H.E. Hansmann, J. Meinke, S. Mohanty (eds.): From Computational Biophysics to Systems Biology, NIC Series 38, pp. 109-113 (2007)
B. Fischer and W.Wenzel
- High throughput in-silico screening with target flexibility. European Conf on Complex Systems (ECCS 2007), Dresden, October 1-5, 2007
Wenzel, W.
- High Throughput Simulations Methoden zum Protein-Liganden Docking. Vortr.: Universität Dortmund, 19.April 2007
Fischer, B.; Wenzel, W.
- Joint experimental and theoretical investigation of the propensity of peptoids as dmg carriers. WSEAS Trans. Biol. Biomed 4 (9), 120 (2007)
T. Schröder, A. Quintilla, J. Setzler, E. Birtalan, W. Wenzel, S. Bräse
- Receptor specific forcefields: improving classical forcefields with quantum mechanical calculafions, in U.H.E. Hansmann, J. Meinke, S. Mohanty (eds.): From Computational Biophysics to Systems Biology, NIC Series 36, 263-265. (2007)
H.E. Pérez Sánchez, B. Fischer, H. Merlitz and W. Wenzel
- Virtual-screening with continuous receptor flexibility. 51st Biophysical Society Annual Meeting, Baltimore, Md., March 3-7, 2007 Biophysical Journal, (2007) Suppl., S.367a
Fischer, B.; Merlitz, H.; Wenzel, W.
- Virtual-screening with continuous receptor flexibility. Biophyical Journal: Suppl. S, 361A (2007)
Fischer B, Merlitz H, Wenzel W
- Conquering the time scale problem in biophysics and materials science. 4th WSEAS Intemat.Conf.on Mathematical Biology and Ecology (MABE'08), Acapuico, MEX, January 25-27, 2008
Wenzel, W.
- High Throughput in-silico Screening against flexible protein receptors", in U.H.E. Hansmann, J. Meinke, S. Mohanty (eds.): From Computational Biophysics to Systems Biology, NIC Series 40, 133-135. (2008)
H.E. Pérez Sánchez, B. Fischer, H. Merlitz and W. Wenzel
- High throughput in-silico screening against flexible protein receptors. From Computational Biophysics to Systems Biology (CBSB08), Workshop, Jülich, May 19-21, 2008
Perez-Sanchez, E.; Fischer, B.; Merlitz, H.; Wenzel, W.
- High throughput in-silico screening with target flexibility. EMBL Conf.on Chemical Biology, Heidelberg, October 8-11, 2008
Kokh, D.; Perez-Sanchez, H.; Wenzel, W.
- Receptor specific scoring functions derived from quantum chemical models improve affinity estimates for in-silico drug discovery. Proteins, Structure, Function and Bioinformatics 70, 1264 (2008)
B. Fischer, K. Fukuzawa, W. Wenzel
