QSAR-guided design and synthesis of novel inhibitors targeting KRAS protein-protein interactions / Benjamin Thäbas Nava Höer. Wuppertal, June 2025
Content
- Acknowledgements
- Abstract
- 1 Biazole and Zafirlukast SAR
- 1.1 Introduction
- 1.1.1 KRAS – A PPI Challenge
- 1.1.2 Primary Structure of RAS
- 1.1.3 Secondary and Tertiary Structure of RAS
- 1.1.4 KRAS in Cancer
- 1.1.5 RAS Cascade
- 1.1.6 SOS Activates RAS
- 1.1.7 GAPs Deactivate RAS
- 1.1.8 Active RASGTP Binds to Downstream Effectors
- 1.1.9 MAPK Pathway
- 1.1.10 PI3K Pathway
- 1.1.11 RAL Pathway
- 1.1.12 Orthosteric RAS PPIIs
- 1.1.13 Allosteric RAS PPIIs
- 1.2 Aim
- 1.3 Results and Discussion
- 1.3.1 Synthesis of JES-248 (14)
- 1.3.2 Attempted Syntheses Towards LDC151135 (12)
- 1.3.3 Synthesis of BNH-039 (37)
- 1.3.4 Derivatisation of Zafirlukast (13)
- 1.3.5 Biochemical Data and Docking Results
- 1.4 Summary and Outlook
- 2 Design of a KRAS PPII Prediction-Synthesis Pipeline
- 2.1 Introduction
- 2.1.1 Medicinal Chemistry in the Age of Data
- 2.1.2 Descriptors and Similarity
- 2.1.3 Quantitative Structure Activity Relationship (QSAR)
- 2.1.4 Characterisation of Molecular Libraries
- 2.1.5 Cyclic Peptides – A Privileged PPII Scaffold
- 2.1.6 Cyclic Peptide KRAS PPIIs
- 2.1.7 Synthesis Routes Towards Cyctetpep
- 2.2 Aim
- 2.3 Results and Discussion
- 2.3.1 Chemical Space Analysis
- 2.3.1.1 Selection of Molecular Libraries
- 2.3.1.2 Structure Preparation
- 2.3.1.3 Comparison of Molecular Descriptors
- 2.3.1.4 Principal Moment of Inertia (PMI)
- 2.3.2 Python QSAR
- 2.3.2.1 ChEMBL Extension
- 2.3.2.2 Feature Selection
- 2.3.2.3 Algorithm Selection
- 2.3.2.4 Structural Perspective of Prediction Accuracy
- 2.3.2.5 Activity Prediction
- 2.3.2.6 Molecular Docking of Cyclic Tri- and Tetrapeptides
- 2.3.2.7 Molecular Dynamics Simulations
- 2.3.3 Cyclic Peptide Syntheses
- 2.3.3.1 Attempted Synthesis of Native Cyctripep 92
- 2.3.3.2 Attempted Synthesis of Native Cyctetpep 93 and 94
- 2.3.3.3 Attempted Imine-Induced Ring Contraction Towards 94
- 2.3.3.4 Synthesis of α-Azido Acids
- 2.3.3.5 Synthesis of α-Amino Acetylenes
- 2.3.3.6 Synthesis of Click Cyctetpep
- 2.3.3.7 Biochemical Data
- 2.4 Summary and Outlook
- 3 Experimental
- 3.1 General Information
- 3.2 Project 1
- 3.3 Project 2
- 3.3.1 General
- 3.3.2 Cheminformatics Software
- 3.3.3 Generation of Cyclic Peptide Libraries
- 3.3.4 Data Preparation
- 3.3.5 Diversity Analysis
- 3.3.6 Python QSAR
- 3.3.7 Rigid Receptor Docking of Cyctetpep Library
- 3.3.8 Molecular Dynamics Simulations
- 3.3.9 Syntheses
- 3.4 Biochemical Assays
- 4 Abbreviations
- 5 References
- 6 Appendix