Recognition of repulsive and attractive regions of selected serotonin receptor binding site using FMO-EDA approach.

The complexes of selected long-chain arylpiperazines with homology models of 5-HT, 5-HT, and 5-HT receptors were investigated using quantum mechanical methods. The molecular geometries of the ligand-receptor complexes were firstly optimized with the Our own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM) method. Next, the fragment molecular orbitals method with an energy decomposition analysis scheme (FMO-EDA) was employed to estimate the interaction energies in binding sites. The results clearly showed that orthosteric binding sites of studied serotonin receptors have both attractive and repulsive regions. In the case of 5-HT and 5-HT two repulsive areas, located in the lower part of the binding pocket, and one large area of attraction engaging many residues at the top of all helices were identified. Additionally, for the 5-HT receptor, the third area of destabilization located at the extracellular end of the helix 6 was found.