Abstract
Drug promiscuity is a double-edged sword where a small molecule acts on multiple biological targets to induce toxicological or therapeutic benefits. It is possible to exploit promiscuity to expand treatment options without the prohibitive costs of designing a new drug. Imatinib is a representative case, exhibiting varied affinities and inhibitions to different kinases. It binds most favorably to Abl and Kit kinases, intermediately to Chk1 and Lck kinases, and least favorably to p38α and Src kinases. The strongly conserved features of the ATP-binding site render imatinib's molecular binding determinants unclear despite over 25 years of interrogation. To address this question, molecular thermodynamics, force distribution analysis, residue sidechain dihedral correlations, and principal component analysis were computed using trajectories from all-atom molecular dynamics simulations in explicit solvent. The results of these simulations agree with experimental affinity and binding data, enabling highly predictive factors for imatinib's binding specificity from free- and bound-state simulations through a global protein network of protein-ligand interactions, changes in sidechain dihedral correlations, and shifts in the secondary motifs modulating binding site access corresponding with well-characterized kinase "breathing motions." The sidechain dihedral correlation network also identifies distal mutants known to reduce patients' imatinib sensitivity. Higher imatinib-kinase affinity trends with a loss in sidechain dihedral correlations and diminished secondary motif migration following binding, corresponding with more restricted configurations, to reduce solvent approach and ATP competition. Lower-affinity proteins show enhanced sidechain dihedral correlation and exaggerated secondary motif motions. This is consistent with a tendency to expose the protein pocket, facilitate solvent entrance, and increase ATP competition. Using imatinib as a model system, this study shows residue correlation, force interaction, and essential principal components can effectively forecast imatinib-kinase binding specificity and introduces an effective approach to repurpose and design high-affinity binders for off-target applications more generally.