Computer-aided methods

Computer-aided methods have become increasingly important not only for lead generation and optimization in the pharmaceutical industry, but also for academic drug research with emphasis on the mechanisms of action. Molecular modeling, molecular dynamics simulations and statistical methods like multiple regression analysis (MRA) and partial least squares (PLS) are applied to investigate

• Ligand-target interactions (e.g., the interaction of agonists and antagonists with receptors or of inhibitors with enzymes)

• Protein-protein interactions with impact on receptor activation and signal transduction

• Quantitative structure-activity relationships (QSAR) including 3D-QSAR with molecular field analysis.

Generally, two classes of approaches are distinguished, namely

• Structure-based methods (docking, virtual screening, de-novo design), if the structure of the target and the ligand binding site is known from PDB structures or homology modeling

• Ligand-based methods (QSAR, similarity and pharmacophore searches), if the binding site is unknown and must be reflected by properties or 3D structures of ligands.

Results from these approaches do not only lead to deeper insight into the mechanisms of action, but also to predictions of more affine, potent and selective ligands or drugs.

In our departement, many of these approaches are used in interdisciplinary medicinal chemistry projects. The hardware (2 SGI Octane, 4 Linux workstations) and software (SYBYL, GROMACS, LUDI, FlexX, in-house QSAR programs) equipment provides sufficient tools for the application of both structure-based and ligand-based methods.

Target models, molecular dynamics simulations, investigation of binding sites, ligand docking, classical and 3D QSAR approaches have been and will be part of our research in the fields of

• Selective histamine H₂ and H₄ receptor ligands

• Neuropeptide Y receptor ligands

• Inhibitors of bacterial and human hyaluronidases

• 5HT_2A receptor agonists (collaboration with Prof. S. Elz, Dept. Pharm./Med. Chem. I)

• Adenylyl cyclase inhibitors (cooperation with Prof. R. Seifert, Inst. Pharmacol., Med. HS Hannover, and Prof. B. König, Dept. Org. Chem.)

• Inhibitors of receptor tyrosine kinases PDGFR and Flt-3 (cooperation with Prof. S. Mahboobi, Dept. Pharm./Med. Chem. I, and Prof. F.-D. Böhmer, Dept. Mol. Cell. Biol., FSU Jena)

Selected publications:

M.E. Silva, R. Heim, A. Strasser, S. Elz, S. Dove, Theoretical studies on the interaction of partial agonists with the 5-HT(2A) receptor. J. Comput. Aided Mol. Des. 25, 51-66 (2011)

J. Geduhn, S. Dove, Y. Shen, W.J. Tang, B. König, R. Seifert, Bis-Halogen-Anthraniloyl-Substituted Nucleoside 5'-triphosphates as Potent and Selective Inhibitors of Bordetella pertussis CyaA. J. Pharmacol. Exp. Ther. 336, 104-115 (2011)

E.H. Schneider, D. Schnell, A. Strasser, S. Dove, R. Seifert, Impact of the DRY Motif and the Missing "Ionic Lock" on Constitutive Activity and G-Protein Coupling of the Human Histamine H4 Receptor. J. Pharmacol. Exp. Ther. 333, 382-392 (2010)

M. Göttle, S. Dove, F. Kees, J. Schlossmann, J. Geduhn, B. König, Y.Q. Shen, W.J. Tang, V. Kaever, R. Seifert, Cytidylyl and Uridylyl Cyclase Activity of Bacillus anthracis Edema Factor and Bordetella pertussis CyaA. Biochemistry 49, 5494-5503 (2010)

P. Ghorai, A. Kraus, T. Birnkammer, R. Geyer, G. Bernhardt, S. Dove, R. Seifert, S. Elz, A. Buschauer, Chiral N-G-acylated hetarylpropylguanidine-type histamine H2 receptor agonists do not show significant stereoselectivity. Bioorg. Med. Chem. Lett. 20, 3173-3176 (2010)

P. Igel, S. Dove, A. Buschauer, Histamine H4 receptor agonists. Bioorg. Med. Chem. Lett. 20, 7191-7199 (2010)

P. Igel, R. Geyer, A. Strasser, S. Dove, R. Seifert, A. Buschauer, Synthesis and Structure-Activity Relationships of Cyanoguanidine-Type and Structurally Related Histamine H4 Receptor Agonists. J. Med. Chem. 52, 6297-6313 (2009)

S. Mahboobi, S. Dove, A. Sellmer, M. Winkler, E. Eichhorn, H. Pongratz, T. Ciossek, T. Baer, T. Maier, T. Beckers, Design of Chimeric Histone Deacetylase- and Tyrosine Kinase-Inhibitors: A Series of Imatinib Hybrides as Potent Inhibitors of Wild-type and Mutant BCR-ABL, PDGF-Rß and Histone Deacetylases. J. Med. Chem. 52, 2265-2279 (2009)

H.M. Taha, J. Schmidt, M. Göttle, S. Suryanarayana, Y. Shen, W.-J. Tang, A. Gille, J. Geduhn, B. König, S. Dove, R. Seifert, Molecular Analysis of the Interaction of Anthrax Adenylyl Cyclase Toxin, Edema Factor, with 2'(3')-O-(N-(methyl)anthraniloyl)-Substituted Purine and Pyrimidine Nucleotides. Mol. Pharmacol. 75, 693-703 (2009)

R. Seifert, S. Dove, Functional Selectivity of GPCR Ligand Stereoisomers: New Pharmacological Opportunities. Mol. Pharmacol. 75, 13-18 (2009)

A. Kraus, P. Ghorai, T. Birnkammer, D. Schnell, S. Elz, R. Seifert, S. Dove, G. Bernhardt, A. Buschauer, N(G)-Acylated aminothiazolylpropylguanidines as potent and selective histamine H2 receptor agonists. ChemMedChem 4, 232-240 (2009)

P. Ghorai, A. Kraus, M. Keller, C. Götte, P. Igel, E. Schneider, D. Schnell, G. Bernhardt, S. Dove, M. Zabel, S. Elz, R. Seifert, A. Buschauer, Acylguanidines as bioisosteres of guanidines: N(G)-acylated imidazolylpropylguanidines, a new class of histamine H2 receptor agonists. J. Med. Chem. 51, 7193-7204 (2008)

H. Preuss, P. Ghorai, A. Kraus, S. Dove, A. Buschauer, R. Seifert, Point Mutations in the Second Extracellular Loop of the Histamine H2 Receptor do not affect the Species-Selective Activity of Guanidine-Type Agonists. Naunyn Schmiedebergs Arch. Pharmacol. 376, 253-264 (2007)

H. Preuss, P. Ghorai, A. Kraus, S. Dove, A. Buschauer, R. Seifert, Mutations of Cys-17 and Ala-271 in the human histamine H2 receptor determine the species-selectivity of guanidine-type agonists and increase constitutive activity. J. Pharmacol. Exp. Ther. 321, 975-982 (2007)

S. Mahboobi, A. Uecker, C. Cenac, A. Sellmer, E. Eichhorn, S. Elz, F.-D. Böhmer, S. Dove, Inhibition of FLT3 and PDGFR tyrosine kinase activity by bis(benzo[b]furan-2-yl)methanones. Bioorg. Med. Chem. 15, 2187-2197 (2007)

M. Göttle, S. Dove, P. Steindel, Y. Shen, W.-J. Tang, J. Geduhn, B. König, R. Seifert, Molecular analysis of the interaction of Bordetella pertussis adenylyl cyclase with fluorescent nucleotides. Mol. Pharmacol. 72, 526-535 (2007)

M. Spickenreither, S. Braun, G. Bernhardt, S. Dove, A. Buschauer, Novel 6-O-acylated vitamin C derivatives as hyaluronidase inhibitors with selectivity for bacterial lyases. Bioorg. Med. Chem. Lett. 16, 5313-5316 (2006)

D.J. Rigden, A. Botzki, M. Nukui, R.B. Mewbourne, E. Lamani, S. Braun, E. v.Angerer, G. Bernhardt, S. Dove, A. Buschauer, M.J. Jedrzejas, Design of New Benzoxazole-2-Thione Derived Inhibitors of Streptococcus pneumoniae Hyaluronan Lyase: Structure of a Complex with a 2-Phenylindole. Glycobiology 16, 757-765 (2006)

S. Mahboobi, A. Uecker, A. Sellmer, C. Cénac, H. Höcher, H. Pongratz, H. Hufsky, A. Trümpler, M. Sicker, F. Heidel, T. Fischer, C. Stocking, S. Elz, F.-D. Böhmer, S. Dove, Novel bis-(1H-indol-2-yl)-methanones as potent inhibitors of FLT3 and platelet-derived growth factor receptor tyrosine kinase. J. Med. Chem. 49, 3101-3115 (2006)

A. Botzki, S. Salmen, G. Bernhardt, A. Buschauer, S. Dove, Structure-based design of bacterial hyaluronan lyase inhibitors. QSAR Comb. Sci. 24, 458-469 (2005)

S. Dove, S. Elz, R. Seifert, A. Buschauer, Structure-Activity Relationships of H2 Receptor Ligands. Mini. Rev. Med. Chem. 4, 941-954 (2004)

S. Dove, Picolinic Acids as Inhibitors of Dopamine β-Monooxygenase: QSAR and Putative Binding Site. Arch. Pharm. (Weinheim) 337, 645-653 (2004)

A. Brennauer, S. Dove, A. Buschauer, Structure-Activity Relationships of Non-Peptide NPY Receptor Antagonists. In: M.C. Michel (Ed.) Neuropeptide Y and Related Peptides, Handbook of Experimental Pharmacology Vol. 162, Springer, Heidelberg, 2004, pp. 506 - 544

A. Botzki, D.J. Rigden, S. Braun, M. Nukui, S. Salmen, J. Hoechstetter, G. Bernhardt, S. Dove, M.J. Jedrzejas, A. Buschauer, L-ascorbic acid-6-hexadecanoate, a potent hyaluronidase inhibitor: X-ray structure and molecular modeling of enzyme-inhibitor complexes. J. Biol. Chem. 279, 45990-45997 (2004)

J. Radons, S. Dove, D. Neumann, R. Altmann, A. Botzki, M.U. Martin, W. Falk, The IL-1 receptor accessory protein TIR domain: analysis of putative interaction sites by in-vitro mutagenesis and molecular modeling. J. Biol. Chem. 278, 49145-49153 (2003)

F.D. Böhmer, L. Karagyozov, A. Uecker, H. Serve, A. Botzki, S. Mahboobi, S. Dove, A single amino acid exchange inverts susceptibility of related receptor tyrosine kinases for the ATP-site inhibitor STI-571. J. Biol. Chem. 278, 5148-5155 (2003)

S. Mahboobi, S. Teller, H. Pongratz, H. Hufsky, A. Sellmer, A. Botzki, A. Uecker, T. Beckers, S. Baasner, C. Schächtele, F. Überall, M.U. Kassack, S. Dove, F.-D. Böhmer, Bis(1H-2-indolyl)methanones as a novel class of inhibitors of the platelet-derived growth factor receptor kinase. J. Med. Chem. 45, 1002-1018 (2002)

M.T. Kelley, T. Bürckstümmer, K. Wenzel-Seifert, S. Dove, A. Buschauer, R. Seifert, Distinct interaction of human and guinea pig histamine H2-receptor with guanidine-type agonists. Mol. Pharmacol. 60, 1210-1225 (2001)

S. Dove, Alignment of molecules by weighted field fit considering active shape. In: H.-D. Höltje, W. Sippl (Eds.) Rational Approaches to Drug Design - 13th European Symposium on QSAR, J. R. Prous Science, S. A., Barcelona, Philadelphia, 2001, pp. 316 - 322

S. Dove, Arzneistoffe aus dem Computer – Modellierung molekularer Schlüssel für biologische Schlösser. Blick in die Wissenschaft (Forschungsmagazin Univ. Regensburg) 13, 22-26 (2001)

S. Dove, M.C. Michel, S. Knieps, A. Buschauer, Pharmacology and quantitative structure-activity relationships of imidazolyl-propylguanidines with mepyramine-like substructures as non-peptide neuropeptide Y Y1 antagonists. Can. J. Physiol. Pharmacol. 78, 108-115 (2000)

A. Buschauer, G. Bernhardt, S. Dove, Neuropeptid Y - NPY-Rezeptoren als Zielstrukturen für neue Arzneistoffe. Pharmazeutische Zeitung 2000, 11-18 (2000)

I. Aiglstorfer, I. Hendrich, C. Moser, G. Bernhardt, S. Dove, A. Buschauer, Structure-Activity Relationships of Neuropeptide Y Y1 Receptor Antagonists Related to BIBP 3226. Bioorg. Med. Chem. Lett. 10, 1597-1600 (2000)

S. Mahboobi, S. Dove, S. Kuhr, A. Popp, Homo-arcyriaflavin: The synthesis of ring-expanded arcyriaflavin analogs. J. Org. Chem. 64, 8130-8137 (1999)

S. Mahboobi, S. Dove, S. Kuhr, H. Pongratz, Synthesis of arcyriarubine regioisomers by Pd(0)-catalysis or via lithiated indole derivatives - conformational analysis by semiempirical and X-ray methods. Pharmazie 54, 820-827 (1999)

S. Dove, A. Buschauer, Improved alignment by weighted field fit in CoMFA of histamine H2 receptor agonistic imidazolylpropyl-guanidines. Quant. Struct.-Act. Relat. 18, 329-341 (1999)

S. Dove, A. Buschauer, Imidazolylpropylguanidines as Histamine H2 Receptor Agonists: 3D-QSAR of a Large Series. Pharm. Acta Helv. 73, 145-155 (1998)

S. Dove, Computermethoden im Arzneimitteldesign. In: L. Lehner, G. Braungart, L. Hitzenberger (Eds.) Multimedia in Lehre und Forschung, Gabler Verlag, Deutscher Universitäts-Verlag, Wiesbaden, 1998, pp. 75 - 88

I. Aiglstorfer, A. Uffrecht, K. Gessele, C. Moser, A. Schuster, S. Merz, B. Malawska, G. Bernhardt, S. Dove, A. Buschauer, Nonpeptide NPY Y1 antagonists: Structure-activity relationships of arginine derivatives and hybrid compounds with arpromidine-like partial structures. Regul. Pept. 75-76 , 9-21 (1998)

M. Müller, S. Knieps, K. Gessele, S. Dove, G. Bernhardt, A. Buschauer, Synthesis and neuropeptide Y Y1 receptor antagonistic activity of N,N-disubstituted  ω-guanidino and ω-aminoalkanoic acid amides. Arch. Pharm. 330, 333-342 (1997)

S. Mahboobi, S. Dove, P.J. Bednarski, S. Kuhr, T. Burgemeister, D. Schollmeyer, X-Ray Crystal Structure of Woodinine and Conformational Analysis by Means of Semiempirical and 1H-NMR Methods. J. Nat. Prod. 60, 587-591 (1997)

S. Dove, A. Buschauer, Stepwise Leave-One-Isomer-Out Free-Wilson Approaches as Preprocessing Tools in QSAR Analysis of Racemates. Quant. Struct.-Act. Relat. 16, 11-19 (1997)

S. Knieps, S. Dove, M.C. Michel, K. Rottmeier, W. Werner, G. Bernhardt, A. Buschauer, ω-Phenyl-ω-(2-pyridyl)alkyl-substituted bisguanidines are moderate neuropeptide Y antagonists. Pharm. Pharmacol. Lett. 6, 27-30 (1996)

S. Knieps, M.C. Michel, S. Dove, A. Buschauer, Non-Peptide Neuropeptide Y Antagonists Derived from the Histamine H2 Agonist Arpromidine: Role of the Guanidine Group. Bioorg. Med. Chem. Lett. 5, 2065-2070 (1995)