Using bitropic ligands that bind at orthosteric and allosteric sites simultaneously, has emerged as a promising drug discovery approach targeting GPCRs. Subtle changes in the structure of orthosteric and allosteric pharmacophores of bitropic ligands often result in selectivity for subtypes of the receptors. The bitropic ligands, including derivatives of phenylpiperazines, have been reported to bind to dopamine receptors, with the therapeutic potential for the treatment of neurological diseases and drug addiction. Here, to elucidate the factors determining binding affinity and selectivity of bitropic ligands, we investigated a large number of phenylpiperazine derivatives with known experimental affinities for dopamine receptor 2 (D2) and 3 (D3) in search of determinants of their affinity and selectivity. Molecular Dynamics (MD) simulations showed that two factors are critical for ligand binding affinities –the ability to make a strong salt bridge with the receptor and the ligand conformation in solution. Further investigation of a set of 90 phenylpiperazines revealed that abundance of folded conformers of the ligand in solution is probably a factor to reduce the affinities of these ligands, indicating populating certain conformers in the unbound state increases the entropic cost of binding bitropic ligands to certain GPCRs. Such disliked conformers might vary among different receptors, but if the rule is known for each receptor, it enables the researchers to quickly identify many weak binders prior to their usually costly chemical synthesis and binding assay. The D2 vs D3 selectivity of bitropic ligands were also investigated using MD simulations of receptors in free form and in complex with different selective ligands. Analysis of these simulations revealed critical residues and structural motifs in the receptors contributing to the selectivity of ligands. Our findings provided insights into the complexity of the factors that determine bitropic ligands binding affinity and selectivity targeting GPCRs.

Affinity and selectivity determinants of bitropic ligands targeting D2 and D3 dopamine receptors

2019 Spring National Meeting

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