Figure 6: Proposed binding mode of pimavanserin at 5-HT_2A (light green) and 5-HT_2CRs (dark green).

Molecular docking and molecular dynamics simulations indicate that pimavanserin engages nearly identical amino acid residues within the binding pocket of 5-HT_2A and 5-HT_2CRs. The primary determinant of selectivity, the extension of the isobutoxybenzyl moiety into the side-extended cavity between TM4 and TM5 (purple circle), as allowed by the small side chain of G^5.42, is conserved in both receptors and is accompanied by a raised rotamer conformation of F^5.38 in both receptor subtypes.