The huge expense of developing a new drug can be wasted if natural mutations of amino acid residues in the targetted protein lead to a loss of drug binding affinity. Rational drug design is a continual struggle, with evolution driving mutations that develop emerging drug resistance into widespread drug inefficacy. We have developed a new free energy method, based on WaterSwap, that can provide drug designers with the insight needed to understand how protein mutations affect drug binding. This method allows the change in binding free energy of the drug associated with the mutation of the protein to be predicted. In addition, as for other Swap-Based methods, this free energy change can be decomposed into components that can be used for visualistion. These components allow the change in binding free energy to be understood in terms of changes in specific ligand-protein interactions, or changes in the solvating water network in the active site. This method allows drug designers to pro-actively screen a new drug computationally against a range of likely protein mutants, thereby enabling the drug designer to get one step ahead of nature. Alternatively, it allows drug designers to investigate the molecular basis for reduced binding affinity in known drug-resistant mutants of a protein. This information would be useful for the development of the subsequent generations of the drug.

Visualising the molecular drivers behind drug resistance

253rd National Meeting (2017)

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