Predicting protein-small molecule, protein-peptide, and antibody-antigen binding free energies (ΔG) is at the heart of rational drug design and of particular use in lead optimization. For example, given a protein target of interest, the difference in ΔG (ΔΔG) between two small molecules (or peptides) of the same chemical series can be determined. Affinity-improving changes are then predicted for different pairs in an iterative way.
BioExcel partners are working on use cases with relevance to the pharmaceutical industry that make use of free energy calculations. Current use cases include the prediction of drug resistance to kinase mutations, lead optimization of peptide series binding to a cancer target, designing antibodies for better antigen binding, and more recently several studies on COVID-19.
The field of free energy calculations has significantly advanced in recent years, making them popular in industry. This is mainly due to improved Molecular Dynamics (MD) simulation packages, more accurate force fields and GPU-acceleration.
BioExcel is at the leading edge of open-source free energy and MD software development: pmx allows easy set up and running of free energy calculations with the MD engine GROMACS. The method is based on thermodynamic integration and is versatile enough to allow calculations with many force fields. A recent large scale study has demonstrated that the approach yields similar accuracy to leading commercial software.
Our work has resulted in strong collaborations with leading pharmaceutical companies to validate and apply these methods in industrial drug discovery settings.
Some of these are highlighted in the following recent publications:
- Gapsys et al. (2015): pmx: Automated Protein Structure and Topology Generation for Alchemical Perturbations. J. Comput. Chem. 36, 348-354.
- Gapsys et al. (2020): Large Scale Relative Protein Ligand Binding Affinities Using Non-Equilibrium Alchemy. Chem. Sci. 11, 1140-1152.
If you would like to know more about using pmx with GROMACS for your industry project, please contact industry@bioexcel.eu.
