The G protein coupled chemokine receptors direct cell migration in development, immunity, and cancer. Two receptors, CCR5 and CXCR4, are also known for their role in HIV infection where they serve as co-receptors for viral entry into host immune cells. Evolved to interact with protein ligands, chemokine receptors typically feature widely open, polar orthosteric binding sites that are challenging targets for small molecule antagonists. Despite decades of efforts, only two small molecules have made it to the clinic thus far: the CCR5 antagonist Maraviroc and the CXCR4 antagonist Plerixafor, for HIV and stem cell mobilization, respectively. CCR2, the receptor that has been actively pursued for autoimmunity and, more recently, for immuno-oncology, has not yielded any clinical candidates thus far. Clinical failures have been attributed to lack of efficacy caused by suboptimal properties of the compounds: poor metabolic stability, high protein binding, inadequate receptor selectivity, or insufficient residence time. Understanding the structural basis of antagonist action at chemokine receptors provides a novel, rational path towards optimization of these properties and, ultimately, development of better clinical candidates.<br/><br/>We were recently successful in determining a crystal structure of CCR2 simultaneously complexed with an orthosteric and allosteric antagonist, and another group crystallized an allosterically inhibited CCR9. The structures revealed the existence of a common druggable site and a novel way of chemokine receptor inhibition: via compound binding at the intracellular cavity. Here we use the CCR2 structure as a launch pad for the development of predictive models of CCR2 complexes with diverse chemotypes of molecules targeting both binding sites. Flexible docking of a wide variety of orthosterics revealed the critical affinity determinants, suggested two distinct structural mechanisms allowing for selectivity over the closely related CCR5, and provided explanation for slow dissociation kinetics, a highly desirable property in anti-CCR2 drug development. Conformational optimization with flexible molecular docking also enabled generation of chemotype-specific models for allosteric antagonists. For both orthosteric and allosteric pocket models, retrospective virtual screening demonstrated high predictive accuracy. Insights into selective and dual targeting of chemokine receptors via allosteric binding site were also obtained.

Orthosteric and allosteric antagonism of chemokine receptors: Structural insights into compound affinity and selectivity

256th National Meeting (2018)

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