3‐Chlorotyramine Acting as Ligand of the D₂Dopamine Receptor. Molecular Modeling, Synthesis and D₂Receptor Affinity

Abstract

We synthesized and tested 3-chlorotyramine as a ligand of the D2 dopamine receptor. This compound displayed a similar affinity by this receptor to that previously reported for dopamine. In order to understand further the experimental results we performed a molecular modeling study of 3-chlorotyramine and structurally related compounds. By combining molecular dynamics simulations with semiempirical (PM6), ab initio and density functional theory calculations, a simple and generally applicable procedure to evaluate the binding energies of these ligands interacting with the D2 dopamine receptors is reported here. These results provided a clear picture of the binding interactions of these compounds from both structural and energetic view points. A reduced model for the binding pocket was used. This approach allowed us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the Quantum Theory of Atoms in Molecules (QTAIM) technique. Molecular aspects of the binding interactions between ligands and the D2 dopamine receptor are discussed in detail. A good correlation between the relative binding energies obtained from theoretical calculations and experimental IC50 values was obtained. These results allowed us to predict that 3-chlorotyramine possesses a significant affinity by the D2 -DR. Our theoretical predictions were experimentally corroborated when we synthesized and tested 3-chlorotyramine which displayed a similar affinity by the D2 -DR to that reported for DA.

Halogen bonding in biological context: a computational study of D2 dopamine receptor

“…However, a more careful inspection of the intermolecular interactions at the substitution point reveals important differences in the interaction patterns. The charge density molecular graphs from Figures as well as previous results show that the ligand phenolic OH groups tend to act either as H‐bond donor against the hydroxyl oxygen of the serine residues in the binding pocket or to form oxygen‐oxygen interactions with them . On the other hand, the halogen rarely interacts with the hydroxyl oxygen of the serine residues.…”

“…Moreover, it has been proven that the sum of the ρ b values (∑ρ) for all the interactions established by the ligand molecule is a good measure of its anchoring strength to the binding pocket. Furthermore, the ∑ρ value corresponding to the interactions established by a particular group of atoms of the ligand molecule is a measure of the anchoring strength of that group to the binding pocket . The ability to decompose the interaction energy in contributions by atom or group of atoms makes the QTAIM analysis particularly useful in analysis, design and optimization of ligand molecules.…”

“…DRD2 halogenated ligands (LX) were compiled from literature and from ZINC database . These compounds were active in direct binding assays to DRD2.…”

“…chlorine ions) were added. For further details of the MD protocol applied see references . A homology model of the long form of the human DRD2 was employed because no crystal structure is yet available for the receptor.…”

Diverse Aromatic Metabolites in the Solitary Tunicate Cnemidocarpa irene

“…We isolated 3-chlorotyramine ( 16 ) for the first time as a natural product . The molecular formula was estimated as C 8 H 10 ClNO from the HRESIMS data.…”