Protein-Protein Interactions in Drug Discovery

Alexander Dömling studied Chemistry and Biology at the Technical University Munich, Germany. After obtaining his PhD under the supervision of Ivar Ugi, he spent a postdoctoral year at the Scripps Research Institute in La Jolla (USA) in the group of Nobel Laureate Barry Sharpless. In 2004 he performed his habilitation at the Technical University of Munich. Since 2006 he teaches and performs research at the University of Pittsburgh in the Department of Pharmacy with secondary appointments in Chemistry and Computational Biology. In 2010 he became full professor receiving his tenure in Pittsburgh. Since 2011 he is chairing the department of Drug Design at the University of Groningen/The Netherlands. Dr. Dömling is founder of several biotech companies, including Morphochem and Carmolex. His research centers around the discovery of antagonists of protein-protein interactions and other biologically active compounds in the therapeutic areas of oncology, infectious and neglected tropical diseases using ?out-of-the-box? software tools and multicomponent reaction chemistries.

• Preface PROTEIN-PROTEIN INTERACTIONS: AN OVERVIEWIntroductionRole of PPIs in Human PhysiologyRegulation of PPIsStructural Features of PPI InterfacesIdentification of PPI InhibitorsConclusions and Outlook PREDICTION OF INTRA- AND INTERSPECIES PROTEIN-PROTEIN INTERACTIONS FACILITATING SYSTEMS BIOLOGY STUDIESIntroduction: Relevance of Interactome Studies to Disease and Drug DiscoveryOur Current Knowledge of Interactomes Identified from Experiments is IncompleteReliability of Interactions Identified ExperimentallyComputational Methods for PPI PredictionSources of Biological Data in Use to Predict PPIsSurvey of Current Interactomes MODULATORS OF PROTEIN-PROTEIN INTERACTIONS: IMPORTANCE OF THREE-DIMENSIONALITYIntroductionStudyDiscussionSummary A LEAP INTO THE CHEMICAL SPACE OF PROTEIN-PROTEIN INTERACTION INHIBITORSIntroductionTypes of InteractionProperties of the InterfaceOrthosteric versus Allosteric ModulationLeap into the iPPI Chemical SpaceCase StudyConclusions INTERACTIVE TECHNOLOGIES FOR LEVERAGING THE KNOWN CHEMISTRY OF ANCHOR RESIDUES TO DISRUPT PROTEIN INTERACTIONSIntroductionDruggable Sites in PPIsStructure-Based Library Design -A Powerful Alternative to High-Throughput ScreeningNew MCR Chemistry to Design PPI AntagonistsVirtual ScreeningNew Interactive Modeling Techniques for Medicinal ChemistsNew Ideas: Hit Rate Validation of Achor-Centered Screening of p53/MDM2/4Summary SH3 DOMAINS AS DRUG TARGETSIntroductionStructureVariabilitySH3 Binding MotifsSelectivityDrug Target SelectionInhibition Strategies: Peptides and Peptoide InhibitorsSmall-Molecule InhibitorsConclusions p53/MDM2 ANTAGONISTS: TOWARDS NONGENOTOXIC ANTICANCER TREATMENTSIntroductionp53/MDM2 PPI is Characterized by Many Cocrystal StructuresNutlins: First-In-Class MDM2 AntagonistsJohnson & Johnson: BenzodiazepinesAmgen: Chromenotriazolopyrimidines & PiperidonesUniversity of Michigan: SpirooxindoleUniversity of Pittsburgh: Ugi Based CompoundsUniversity of Newcastle: Some Scaffolds With No Structural Biology InformationOutlook INHIBITION OF LFA-1K/ICAM INTERACTION FOR THE TREATMENT OF AUTOIMMUNE DISEASESIntroductionIntegrin Structure and ActivationDirect Inhibition of the LFA-1/ICAM InteractionAllosteric Inhibitors of the LFA-1/ICAM Interaction -IDAS SiteSummary THE PIF POCKET OF AGC KINASES: A TARGET SITE FOR ALLOSTERIC MODULATORS AND PROTEIN-PROTEIN INTERACTION INHIBITORSIntroductionDiscovery and Physiological Functions of the PIF PocketProperties of the PIF Pocket Relevant to Drug DevelopmentSmall-Molecule PIF Pocket LigandsPotential Supportive Effects Enhancing the Cellular Activity of PIF Pocket-Binding ModulatorsConclusions RETOSIBAN AND EPELSIBAN: POTENT AND SELECTIVE ORALLY AVAILABLE OXYTOCIN ANTAGONISTSIntroductionAryl-2,5-DKP Template Discovery and Initial Structure-Activity Relationship StudiesSynthesis of the RRR and RRS 6-Indanyl-3-isobutyl-7-aryl-2,5-DKP Secondary AmidesComparison of Crystal Structures of Oxytocin and 2,5-DKPsPharmacokinetics and Property-Based DesignIn Vivo Potency of 2',4'-Diflurophenyl Dimethylamide 22Synthesis of Tertiary AmidesSummary of Lead Oxytocin Antagonist 2',4'-Diflurophenyl Dimethylamide 22Further Modifications, Five- and Six-Membered Heterocyclic DerivativesFive-Membered Heterocyclic Derivatives and RetosibanSummary of Lead Oxytocin Antagonist Retosiban 56Six-Membered Heterocyclic Derivatives and EpelsibanSummary of Lead Oxytocin Antagonist Epelsiban 77Comparison of Lead CompoundsConclusions PEPTIDIC INHIBITORS OF PROTEIN-PROTEIN INTERACTIONS FOR CELL ADHESION RECEPTORS: RGD PEPTIDES AND BEYONDIntroductionFrom the Discovery of the RGD Motif in FN to the First Selective Cyclic RGD PeptideN-Methylation of c(RGDfV): Cilengitide and BeyondisoDGR Sequence as a New Integrin-Binding MotifConclusions REPLACE STRATEGY FOR GENERATING NON-ATP-COMPETITIVE INHIBITORS OF CELL CYCLE PROTEIN KINASESIntroductionInhibition of CDKs Through the Cyclin GrooveInhibitors of PLKsConclusions Index