title: Limiting the Number of Potential Binding Modes by Introducing Symmetry into Ligands: Structure-Based Design of Inhibitors for Trypsin-Like Serine Proteases.
abstract: In the absence of X-ray data, the exploration of compound binding modes continues to be a challenging task. For structure-based design, specific features of active sites in different targets play a major role in rationalizing ligand binding characteristics. For example, dibasic compounds have been reported as potent inhibitors of various trypsin-like serine proteases, the active sites of which contain several binding pockets that can be targeted by cationic moieties. This results in several possible orientations within the active site, complicating the binding mode prediction of such compounds by docking tools. Therefore, we introduced symmetry in bi- and tribasic compounds to reduce conformational space in docking calculations and to simplify binding mode selection by limiting the number of possible pocket occupations. Asymmetric bisbenzamidines were used as starting points for a multistage and structure-guided optimization. A series of 24 final compounds with either two or three benzamidine substructures was ultimately synthesized and evaluated as inhibitors of five serine proteases, leading to potent symmetric inhibitors for the pharmaceutical drug targets matriptase, matriptase-2, thrombin and factor Xa. This study underlines the relevance of ligand symmetry for chemical biology.
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).|Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, University of Bonn, Dahlmannstr. 2, 53113 Bonn (Germany).
authors.forename: Norbert
authors.initials: N
authors.lastname: Furtmann
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).
authors.forename: Daniela
authors.initials: D
authors.lastname: Häußler
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).
authors.forename: Tamara
authors.initials: T
authors.lastname: Scheidt
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).
authors.forename: Marit
authors.initials: M
authors.lastname: Stirnberg
authors.affiliation: Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, 35032 Marburg (Germany).
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, University of Bonn, Dahlmannstr. 2, 53113 Bonn (Germany).
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany). guetschow@uni-bonn.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
mesh_terms: D001550:Benzamidines / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D057786:Peptidomimetics / Q000737:chemistry*; D011485:Protein Binding; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry*; D013917:Thrombin / Q000737:chemistry*
chemical_list: D001550:Benzamidines; D008024:Ligands; D008565:Membrane Proteins; D057786:Peptidomimetics; D015842:Serine Proteinase Inhibitors; C114880:trypsin-like serine protease; D012697:Serine Endopeptidases; C485595:matriptase; C467801:matriptase 2; D013917:Thrombin
keywords: benzamidines; chirality; peptidomimetics; serine proteases; symmetry