Progress in medicinal chemistry. Volume 60 /

Detalles Bibliográficos
Clasificación:Libro Electrónico
Otros Autores: Cox, Brian (Chemist) (Editor ), Witty, D. R. (David R.) (Editor )
Formato: Electrónico eBook
Idioma:Inglés
Publicado: Amsterdam, Netherlands : Elsevier, 2021.
Colección:Progress in medicinal chemistry ; volume 60
Temas:
Pharmaceutical chemistry.
Chemistry, Pharmaceutical
Chimie pharmaceutique.
Pharmaceutical chemistry
Acceso en línea:Texto completo
Tabla de Contenidos:
  • Intro
  • Progress in Medicinal Chemistry
  • Copyright
  • Contents
  • Contributors
  • Preface
  • Chapter Two: PROTACs, molecular glues and bifunctionals from bench to bedside: Unlocking the clinical potential of cataly ...
  • 1. PROTACs: Heterobifunctional molecules hijacking the UPS
  • 1.1. Historical timeline and milestones of PROTACs
  • 1.2. Advantages of PROTACs over small molecule drugs
  • 1.3. Key parameters to evaluate PROTAC activity
  • 1.4. General considerations for PROTAC design
  • 1.5. PROTACs and `molecular glues: Two sub-modalities for targeted degradation emerge
  • 2. From concept to practice: Challenges and opportunities in PROTAC development
  • 2.1. Considerations and methodologies for POI and E3 ligase selection
  • 2.1.1. Genetic fusion technologies
  • 2.1.2. Macromolecular strategies
  • 2.1.3. Protein modification strategies to expand the E3 ligase toolbox
  • 2.2. Optimisation of PROTAC properties and the importance of linkerology
  • 2.2.1. Assays to evaluate physicochemical properties of PROTACs in vitro
  • 2.2.2. PROTAC linkerology
  • 2.3. Assessment of targeted protein degradation in cells
  • 2.3.1. Immunoassays
  • 2.3.2. Reporter assays
  • 2.3.2.1. Fluorescence-based reporter assays
  • 2.3.2.2. Luminescence-based reporter assays
  • 2.3.3. Mass spectrometry
  • 2.3.4. Ubiquitin-proteasome system dependency assays
  • 2.4. Quantification of key intracellular events for targeted protein degradation
  • 2.4.1. Ternary complex formation
  • 2.4.2. Target ubiquitination
  • 2.5. PROTAC development workflow
  • 3. Scope of targeted protein degradation
  • 3.1. Proteins degraded: An overview
  • 3.2. Oncology targets at the forefront of TPD
  • 3.3. The search for novel E3 ligase ligands: Opportunities in TPD
  • 3.3.1. Chemoproteomics as a tool for the identification of E3 ligase ligands
  • 3.3.2. Rational identification of molecular glues.
  • 3.4. Degrading `challenging targets
  • 3.4.1. Signal transducer and activator of transcription 3
  • 3.4.2. Tau
  • 4. Current progress in PROTAC translational research
  • 4.1. Transitioning PROTACs from the bench to the clinic
  • 4.1.1. The hurdles of pharmacokinetic optimisation
  • 4.1.2. PROTACs degrade target proteins in vivo
  • 4.2. PROTACs in clinical trials: The race for the first approval
  • 5. Emerging approaches in targeted protein degradation
  • 5.1. Targeted delivery and conditional activation of PROTACs
  • 5.1.1. Tissue-selective protein degradation: Antibody-PROTAC conjugates
  • 5.1.2. Spatiotemporal control of protein degradation: Conditional activation of PROTACs with light
  • 5.2. Alternative approaches for targeted protein degradation
  • 5.2.1. Proteasomal degradation: BioPROTACs
  • 5.2.2. Lysosomal degradation: LYTACs, AUTACs and ATTECs
  • 5.2.2.1. LYTACs: Protein degradation through the endosome/lysosome pathway
  • 5.2.2.2. AUTACs and ATTEC: Protein degradation through the autophagy pathway
  • 5.3. From chimeric degraders to heterobifunctionals: Expanding the proximity-induction paradigm
  • 5.3.1. RIBOTACs
  • 5.3.2. Heterobifunctional molecules: Expanding the post-translational modifiers toolbox
  • 6. Summary
  • Appendix
  • A. List of abbreviations
  • B. List of protein ID
  • References
  • Chapter Three: Automated and enabling technologies for medicinal chemistry
  • 1. Introduction
  • 2. History of automation in medicinal chemistry
  • 2.1. Early synthesis technologies
  • 2.2. Development of automated purification techniques
  • 2.3. From manual to automated analysis
  • 3. The current state of automation and established technologies in medicinal chemistry
  • 3.1. Analyse and design-Software tools
  • 3.2. Make-Reaction planning tools
  • 3.3. Make-Synthesis tools
  • 3.4. Make-Work-up tools
  • 3.5. Make-Automated purification systems.
  • 3.6. Make-Automated analysis techniques
  • 4. Automation gaps and emerging technologies
  • 4.1. Artificial intelligence and machine learning
  • 4.2. Fully automated integrated synthesis platforms
  • 4.3. Closed-loop drug discovery
  • 4.4. Gaps and outlook for automated technologies in medicinal chemistry
  • 5. Medicinal chemists vs machines: What the future holds
  • References
  • Chapter Four: Use of molecular docking computational tools in drug discovery
  • 1. Introduction
  • 2. Molecular docking
  • 2.1. Theory of docking
  • 2.2. Searching algorithm
  • 2.2.1. Systematic methods
  • 2.2.2. Stochastic methods
  • 2.2.3. Scoring functions
  • 2.2.3.1. Tailored scoring functions
  • 2.3. Practical aspects in molecular docking
  • 2.3.1. Protein preparation
  • 2.3.1.1. Protonation state
  • 2.3.1.2. Binding site definition and cavity detection
  • 2.3.1.3. Protein flexibility
  • 2.3.1.3.1. Soft docking and side chain rotamer libraries
  • 2.3.1.3.2. Ensemble docking
  • 2.3.1.4. Structural water molecules
  • 2.3.1.4.1. How to recognise active water?
  • 2.3.2. Ligand preparation
  • 2.4. Small molecule databases
  • 2.4.1. ZINC database
  • 2.4.2. ENAMINE database
  • 2.4.3. NCI open database
  • 2.4.4. ChEMBL
  • 2.4.5. DrugBank
  • 2.4.6. ASINEX database
  • 2.4.7. Cambridge structural database (CSD)
  • 2.4.8. PubChem
  • 3. Fragment-based screening
  • 4. Protein-protein docking
  • 5. Protein-peptide docking
  • 6. Nucleic acid docking
  • 7. Current challenges
  • 7.1. Blind docking
  • 7.2. Covalent docking
  • 7.3. Reverse docking
  • 8. Looking forward
  • References
  • Chapter Five: An industrial perspective on co-crystals: Screening, identification and development of the less utilised so ...
  • 1. Introduction
  • 2. What are co-crystals?
  • 2.1. History and discovery
  • 2.1.1. Crystal engineering
  • 2.1.2. Cinnamic acid example
  • 2.2. The salt co-crystal continuum.
  • 3. Intellectual property and regulatory perspective on co-crystals
  • 4. Generation, characterisation, and development of co-crystals
  • 4.1. Designing screens and synthons
  • 4.1.1. Supramolecular synthons
  • 4.2. Screening by grinding
  • 4.2.1. Synthesis of pharmaceutical co-crystals
  • 4.2.2. Mechanochemical co-crystal screening
  • 4.2.3. Liquid-assisted grinding (LAG)
  • 4.2.4. In situ monitoring
  • 4.3. Screening by solution methods
  • 4.3.1. Evaporative crystallisation
  • 4.3.2. Cooling crystallisation
  • 4.3.3. Anti-solvent crystallisation
  • 4.3.4. Solution-mediated phase transformation (slurry conversion) methods
  • 4.4. Characterisation of co-crystals
  • 4.4.1. Single crystal X-ray diffraction (SCXRD)
  • 4.4.2. Powder X-ray diffraction (XRPD)
  • 4.4.3. Solid-state NMR
  • 4.4.4. Infrared and Raman spectroscopy
  • 4.5. Importance of phase diagrams
  • 4.5.1. Binary phase diagrams
  • 4.5.2. Ternary phase diagrams
  • 4.6. Scaling up of co-crystals
  • 4.6.1. Mechanochemistry
  • 4.6.2. Twin screw extrusion (TSE)
  • 4.6.3. Resonant acoustic mixing (RAM)
  • 4.6.4. High shear granulation (HSG)
  • 4.6.5. Solution based scale up
  • 4.6.6. Solubility
  • 4.6.7. Nucleation and seeding
  • 4.6.8. Crystal growth
  • 4.6.9. Process analytical technologies
  • 4.6.10. Case studies
  • 4.7. Formulating co-crystals
  • 5. Application of co-crystals
  • 5.1. Processability
  • 5.2. Solubility
  • 5.3. Bioavailability
  • 5.4. Improving formulation
  • 5.5. Permeability
  • 5.6. Drug-drug co-crystals
  • 5.6.1. Dual action
  • 5.6.2. Non-commercial drug-drug co-crystals
  • 5.7. Purification and chiral resolution
  • 5.7.1. Diastereomeric co-crystals
  • 5.7.2. Preferential crystallisation of co-crystals
  • 6. Summary and looking forward
  • References.

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