Molecular modeling of antipsychotic drugs and G protein coupled receptors

The three dimensional structure, electrostatic potentials and molecular dynamics of a series of tricyclic antipsychotic drugs and metabolites were examined by computer graphics and molecular modeling techniques. Three dimensional models of the 5-HT1A and 5-HT2 receptor and of the dopamine D2 receptor were constructed from the amino acid sequences. The receptor models have strongly negative electrostatic potentials around the synaptic domains and a postulated ligand binding site. This indicates that protonated ligands are attracted to these receptors by electrostatic forces. Pharmacologically inactive trans(E)-thioxanthenes and phenothiazine ring sulphoxides had strongly negative electrostatic potentials around a part of the ring system. This may weaken their electrostatic interactions with the D2 receptor, and be the reason for their lack of potency in D2 receptor binding and related pharmacological tests. Molecular dynamics simulations in aqueous solution demonstrated that both the side chains and the tricyclic ring systems of the drugs are highly flexible, and move between different conformations in picoseconds.