Abstract
The dynamic property of a ligand in the receptor-bound state is an important metric to characterize the interactions in the ligand–receptor interface, and the development of an experimental strategy to quantify the amplitude of motions in the bound state is of importance to introduce the dynamic aspect into structure-guided drug development (SGDD). Fluorine modifications are frequently introduced at the hit-to-lead optimization stage to enhance the binding potency and other characteristics of a ligand. However, the effects of fluorine modifications are generally difficult to predict, owing to the pleiotropic nature of the interactions. In this study, we report an NMR-based approach to experimentally evaluate the local dynamics of trifluoromethyl (CF3)-containing ligands in the receptor-bound states. For this purpose, the forbidden coherence transfer (FCT) analysis, which has been used to study the dynamics of methyl moieties in proteins, was extended to the 19F nuclei of CF3-containing ligands. By applying this CF3–FCT analysis to a model interaction system consisting of a ligand, AST-487, and a receptor, p38α, we successfully quantified the amplitude of the CF3 dynamics in the p38α-bound state. The strategy would bring the CF3-containing ligands within the scope of dynamic SGDD to improve the affinity and specificity for the drug-target receptors.
Highlights
The affinity and specificity of small molecules to their targets need to be improved in the hit-to-lead and the lead optimization processes in drug development
Ligands with larger enthalpic contributions to the receptor-binding free energy are expected to show better target specificity and to be less susceptible to drug-resistance mutations [2,3,4]. Such enthalpy-driven bindings are usually derived from multiple site-specific intermolecular interactions, such as hydrogen bonds and van der Waals interactions
The current structure-guided drug development (SGDD) approaches, which rely largely on static structures, would be improved by taking the dynamic aspects of interactions into account and by developing experimental strategies to quantify the amplitude of motions
Summary
The affinity and specificity of small molecules to their targets need to be improved in the hit-to-lead and the lead optimization processes in drug development. The CH3 –FCT analyses were applied to a μM-affinity peptide ligand that binds to a drug-target kinase, to identify the methyl-bearing residues with a large motional amplitude and low surface complementarity in the kinase-bound state. The strong electron-withdrawing propensity of fluorine affects the interactions of remote functional groups, and the bulky fluorine substituent often modulates the dynamics of ligands in both the free and bound states. Such a pleiotropic nature makes the effects of fluorine incorporation difficult to predict. The comparison of the FCT profile of the ligand in the non-deuterated receptor-bound state, relative to that of the perdeuterated receptor-bound state, indicated that the strategy would provide the surface complementarity information at the CF3 site
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