BIOMAT Database Logo BIOMAT Database Logo

Rational design, synthesis, and X-ray structure of selective noncovalent thrombin inhibitors. 1998

J Wagner, and J Kallen, and C Ehrhardt, and J P Evenou, and D Wagner
Novartis Pharma AG, CH-4002 Basel, Switzerland.

We have designed, synthesized, and tested in vitro a novel class of noncovalent thrombin inhibitors. The main feature of these inhibitors is a 6,5-fused bicyclic core structure that fills the S2 pocket of the active site of thrombin. The bicycle introduces conformational constraint into the ligand and locks the Xaa-Pro amide bond into the desired trans configuration. Among the known ring systems, we selected by molecular modeling the 7-thiaindolizidinones (BTD) as our basic template. The influence of several structural features was analyzed: the length of the argininal side chain, the stereochemistry at C6, and the importance of making optimal use of the S3 pocket. Finally, an X-ray crystal structure of inhibitor 15 bound to thrombin was obtained at a resolution of 2.3 A. These designed thrombin inhibitors, which were prepared by an efficient synthesis, showed high selectivity over trypsin and other serine proteases. Further derivation based on the information obtained by X-ray crystallography should certainly allow to improve the potency.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D008968 Molecular Conformation The characteristic three-dimensional shape of a molecule. Molecular Configuration,3D Molecular Structure,Configuration, Molecular,Molecular Structure, Three Dimensional,Three Dimensional Molecular Structure,3D Molecular Structures,Configurations, Molecular,Conformation, Molecular,Conformations, Molecular,Molecular Configurations,Molecular Conformations,Molecular Structure, 3D,Molecular Structures, 3D,Structure, 3D Molecular,Structures, 3D Molecular
D002417 Cattle Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor. Beef Cow,Bos grunniens,Bos indicus,Bos indicus Cattle,Bos taurus,Cow,Cow, Domestic,Dairy Cow,Holstein Cow,Indicine Cattle,Taurine Cattle,Taurus Cattle,Yak,Zebu,Beef Cows,Bos indicus Cattles,Cattle, Bos indicus,Cattle, Indicine,Cattle, Taurine,Cattle, Taurus,Cattles, Bos indicus,Cattles, Indicine,Cattles, Taurine,Cattles, Taurus,Cow, Beef,Cow, Dairy,Cow, Holstein,Cows,Dairy Cows,Domestic Cow,Domestic Cows,Indicine Cattles,Taurine Cattles,Taurus Cattles,Yaks,Zebus
D006146 Guanidines A family of iminourea derivatives. The parent compound has been isolated from mushrooms, corn germ, rice hulls, mussels, earthworms, and turnip juice. Derivatives may have antiviral and antifungal properties.
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013237 Stereoisomerism The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed) Molecular Stereochemistry,Stereoisomers,Stereochemistry, Molecular,Stereoisomer
D013844 Thiazoles Heterocyclic compounds where the ring system is composed of three CARBON atoms, a SULFUR and NITROGEN atoms. Thiazole

Related Publications

J Wagner, and J Kallen, and C Ehrhardt, and J P Evenou, and D Wagner
Structure-Based Design of Selective Noncovalent CDK12 Inhibitors.
February 2018, ChemMedChem,
J Wagner, and J Kallen, and C Ehrhardt, and J P Evenou, and D Wagner
Phenolic P2/P3 core motif as thrombin inhibitors--design, synthesis, and X-ray co-crystal structure.
February 2006, Bioorganic & medicinal chemistry letters,
J Wagner, and J Kallen, and C Ehrhardt, and J P Evenou, and D Wagner
Molecular recognition at the thrombin active site: structure-based design and synthesis of potent and selective thrombin inhibitors and the X-ray crystal structures of two thrombin-inhibitor complexes.
April 1997, Chemistry & biology,
J Wagner, and J Kallen, and C Ehrhardt, and J P Evenou, and D Wagner
Rational design and synthesis of selective BACE-1 inhibitors.
February 2004, Bioorganic & medicinal chemistry letters,
J Wagner, and J Kallen, and C Ehrhardt, and J P Evenou, and D Wagner
Structure-based design of highly selective β-secretase inhibitors: synthesis, biological evaluation, and protein-ligand X-ray crystal structure.
November 2012, Journal of medicinal chemistry,
J Wagner, and J Kallen, and C Ehrhardt, and J P Evenou, and D Wagner
Design and synthesis of potent and selective macrocyclic thrombin inhibitors.
August 2003, Bioorganic & medicinal chemistry letters,
J Wagner, and J Kallen, and C Ehrhardt, and J P Evenou, and D Wagner
Design and synthesis of potent and highly selective thrombin inhibitors.
November 1994, Journal of medicinal chemistry,
J Wagner, and J Kallen, and C Ehrhardt, and J P Evenou, and D Wagner
Anilinopyrazole as selective CDK2 inhibitors: design, synthesis, biological evaluation, and X-ray crystallographic analysis.
September 2003, Bioorganic & medicinal chemistry letters,
J Wagner, and J Kallen, and C Ehrhardt, and J P Evenou, and D Wagner
The X-ray structure of RANTES: heparin-derived disaccharides allows the rational design of chemokine inhibitors.
November 2004, Structure (London, England : 1993),
J Wagner, and J Kallen, and C Ehrhardt, and J P Evenou, and D Wagner
Design, synthesis and biological evaluation of selective boron-containing thrombin inhibitors.
July 1999, Bioorganic & medicinal chemistry,
Copied contents to your clipboard!