Polymorphic interruption of molecular allosteric pathways in mitotic kinesin-5: comparison of experiment and algorithmic prediction

Abstract

Inter-individual variability in drug response arises from genetic differences associated with small-molecule binding and biochemical response upon binding. These genetic variations, in the form of single-nucleotide polymorphisms, can increase or decrease inhibitor efficacy. However, a major challenge in targeted drug development is prediction of which mutations, distant from the drug-binding site, will alter enzymatic response. Herein we use a published amino acid atlas of human Eg5 kinesin residues, that are energetically wired from an allosteric inhibitor binding site, as a map to predict which human polymorphisms would give rise to inhibitor resistance.