Computational structure-based drug design for the identification and characterization of new inhibitors of antimicrobial targets
Prof. Dr. Christoph Sotriffer
The aim of project C7 is to characterize the interactions of small-molecule inhibitors with antimicrobial target enzymes by means of computational structure-based drug design. Binding site analyses, docking and scoring methods, as well as molecular dynamics simulations will be applied to investigate the binding mode of known ligands, to define possibilities for improving inhibition, and to propose new scaffolds for putative inhibitors. Methods for the consideration of protein flexibility, for the prediction of selectivity, and for the estimation of entropic effects will be tested and applied.
The work will be focused primarily on the enoyl-ACP-reductase (InhA) and the β-ketoacyl-ACP-synthase I (KasA) from Mycobacterium tuberculosis. Both proteins are essential enzymes of the fatty acid biosynthesis. By means of virtual screening and structure-based drug design, new lead structures for potential inhibitors of InhA will be searched. Candidate molecules will be experimentally tested and evaluated in the projects A4 (Schirmeister) and B7 (Kisker). For the KasA target, the cerulenin derivatives investigated in project A1 (Holzgrabe) will be characterized and further optimized in cooperation with project C3 (Engels). For both targets it appears likely that the flexibility of the binding pocket plays an important role with respect to ligand binding. This will be investigated in detail by means of molecular dynamics simulations and the corresponding results will be used for further design attempts. Aspects of selectivity and possibilities for “multiple targeting” will also be considered. In cooperation with project C3 (Engels) it is planned to develop improved scoring functions for the investigated targets.
Besides these studies focused on inhibitor design, the C,C- and N,C-coupled naphthyl¬isoquinolines will be investigated with respect to possible target interactions. In particular, docking studies to potential target proteins will be carried out to support the efforts of project A2 (Bringmann) dedicated to the identification of the target of these antiplasmodial compounds. Additional work is planned to support the rational design of Mip-specific PPIase-inhibitors without immunosuppressive side effects envisaged by project C2 (Faber/Jakob/ Haase) in collaboration with projects A1 (Holzgrabe) and B1 (Hacker/Steinert). This study will be based on the structural characterization of the Mip-protein achieved in the last funding period.
Finally, contributions to an improved thermodynamic characterization of protein-ligand complexes shall be made. In this context, it is planned to use Poisson-Boltzmann calculations to analyze protonation changes upon ligand binding in order to allow for an unambiguous partitioning of calorimetric data from project B7 (Kisker) into enthalpies and entropies of binding. In addition, methods for the estimation of entropic contributions of water molecules in protein-ligand complexes based on molecular dynamics simulations will be tested and applied.
Selected, SFB-relevant Publications
B. Merget, D. Zilian, T. Muller, C. A. Sotriffer; MycPermCheck: the Mycobacterium tuberculosis permeability prediction tool for small molecules. Bioinformatics 2013, 29, 62-68. doi:10.1093/bioinformatics/bts641
M. W. Hirschbeck, J. Kuper, H. Lu, N. Liu, C. Neckles, S. Shah, S. Wagner, C. A. Sotriffer, P. J. Tonge, C. Kisker; Structure of the Yersinia pestis FabV Enoyl-ACP Reductase and Its Interaction with Two 2-Pyridone Inhibitors. Structure 2012, 20, 89-100.
B. Schaefer, C. Kisker, C. A. Sotriffer; Molecular dynamics of Mycobacterium tuberculosis KasA: implications for inhibitor and substrate binding and consequences for drug design. J Comput Aided Mol Des 2011, 25, 1053-1069.
C. Juli, M. Sippel, J. Jager, A. Thiele, M. Weiwad, K. Schweimer, P. Rosch, M. Steinert, C. A. Sotriffer, U. Holzgrabe; Pipecolic acid derivatives as small-molecule inhibitors of the Legionella MIP protein. J Med Chem 2011, 54, 277-283.
D. Cappel, R. Wahlstrom, R. Brenk, C. A. Sotriffer; Probing the dynamic nature of water molecules and their influences on ligand binding in a model binding site. J Chem Inf Model 2011, 51, 2581-2594.
C. A. Sotriffer; Induced-fit effects in docking: What is possible and what is not? Curr Top Med Chem 2011, 11, 179-191.
C. Sotriffer, H. Matter; The challenge of affinity prediction: Scoring functions for structure-based virtual screening. In: Virtual Screening. Principles, Challenges, and Practical Guidelines, Sotriffer, C., Ed., Vol. 48 of Methods and Principles in Medicinal Chemistry, Mannhold, R., Kubinyi, H., Folkers, G., Series Ed.s, Wiley-VCH: Weinheim, 2011; pp 179-221.
H. Matter, C. Sotriffer; Applications and success stories in virtual screening. In: Virtual Screening. Principles, Challenges, and Practical Guidelines, Sotriffer, C., Ed., Vol. 48 of Methods and Principles in Medicinal Chemistry, Mannhold, R., Kubinyi, H., Folkers, G., Series Ed.s, Wiley-VCH: Weinheim, 2011; pp 319-358.