Download the full description of this project: ESR10: Fragment evolution platform – molecular simulations
Hydrogen Bonds as determinants of structural stability: implications for ligand design
The aim of the project is to develop new computational approaches for structure-based drug design. These tools will also be used to investigate new properties of macromolecular complexes and their role in molecular recognition.
Our methods rely on a fundamental property of protein-ligand complexes that has been neglected in drug design so far: structural stability, which describes the resistance of the system to structural changes. Thanks to sharp distance and angular dependencies1, stability can be provided by hydrogen bonds. Certain hydrogen bonds present strong opposition to small structural distortions and can act as kinetic traps2, thus influencing the whole dissociation process. This concept has been implemented in the molecular-dynamics based method, Dynamic Undocking (DUck)3, which allows to assess the structural stability of the complex by calculating the work used in the process of breaking the hydrogen bond (WQB).
In the first part of the project we performed a first large-scale assessment of robustness of hydrogen bonds on a set of 77 protein-ligand complexes (341 hydrogen bonds)4 sourced from the Iridium data set5. We have shown that hydrogen bond-driven structural stability is very common. Stable bonds can be found in 75% of complexes and tend to group in fragment-sized structural anchors. Additional calculations have shown that we can modulate the stability of the bond by modifying the structure of ligand. Manipulating the local environment around the bond has important implications for structural stability, and is a useful drug design principle.
In the second part of the project we used the same data set to evaluate the usefulness of structural stability in binding mode prediction. Post-docking pose evaluation with DUck was performed on a set of binding modes generated with rDock6. The results show that DUck is equally good as rDock at selecting poses. Additionally, the performance of DUck surpasses the docking software in predicting the binding mode of the structural anchor. That has been confirmed on the set of protein-fragment complexes, gathered in SERAPhiC data set7. DUck is also more resistant to conformational changes in the receptor, which was confirmed in cross-docking experiment.
The project branched into a few subprojects, which were performed by other members of the group. One of them is attempting to find a relationship between structural stability and the binding free energy on the set of carefully selected activity cliffs. The other uses a large collection of DUck simulation data and machine learning approaches to construct a predictor of structural stability of macromolecular complexes.
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- ESR1: 3D Fragments with small aliphatic rings - David Hamilton
- ESR2: Novel 3D fragments - Hanna Francesca Klein
- ESR3: Warhead Library of Covalent Fragment Binders - Aaron Keeley
- ESR4: Development of FBLD techniques for Intrinsically Disordered Proteins - Darius Vagrys
- ESR5: Biophysics Based FBLD - Sébastien Keiffer
- ESR6: FBLD experimental methods - Edward Fitzgerald
- ESR7: Understanding PDE binding kinetics - Pierre Boronat
- ESR8: Virtual Screening of Fragment Libraries of Covalent Binders - Andrea Scarpino
- ESR9: Fragment evolution platform - chemical navigation - Moira Rachman
- ESR11: Fragment-based approaches to identify novel PPI inhibitors - Lorena Zara
- ESR12: Covalent fragments to activate industrial enzymes - Eleni Makraki
- ESR13: Fragment-based assessment of new antibiotic target - Bas Lamoree
- ESR14: Targeting allosteric pockets with FBLD - Lena Münzker
- ESR15: Science, Business & Innovation in the pharmaceutical sciences - Angelo Kenneth Romasanta