Drug Resistance and Drug Design

Drug resistance is one of the most serious health problems facing humanity in the 21st century. This problem represents an enormous challenge to rational drug design, since the pathogen can mutate randomly. Thus, it is unclear what the next target for new drugs would be. Here, we suggest a paradigm shift in fighting drug resistance, by exploiting the fact that the survival of the pathogen depends on the ability of the targeted proteins to mutate to a form that will allow it to keep a high “vitality value” (by reducing the binding affinity of the given drug) while still retaining its catalytic function. We have been trying to attack this “Achilles heel” by developing effective computational approaches for evaluating the vitality values and the more general survival function that reflects additional constraints on folding and stability. These approaches1,2. should allow us to simulate drug resistance on a molecular level and to advance new inhibition strategies to which the pathogen will not easily adapt.
As a part of the main direction of fighting drug resistance we have been working for a long time on improving and validating methods for evaluating the energetics of drug binding (e.g. 3,4).