Structural insight into receptor-selectivity for lurasidone

Structure versus function—The impact of computational methods on the discovery of specific GPCR–ligands

“…In another study MD simulations were applied for the refinement of homology models of aminergic GPCRs (D 2 , 5-HT 2A , 5-HT 7 , H 1 and M 1 ) in complex with several docked antipsychotics. The results could nicely explain the selectivity profile of lurasidone in comparison with olanzapine and ziprasidone[19].…”

G-Protein/β-Arrestin-Linked Fluctuating Network of G-Protein-Coupled Receptors for Predicting Drug Efficacy and Bias Using Short-Term Molecular Dynamics Simulation

“…We used the same conformation and orientation of the ligand as in the crystal structure if the crystal structures of the ligand-bound β 2 AR/β 1 AR had been determined, which was the case for BI-167107 (PDB ID: 3SN6), carazolol (2RH1), ICI-118551 (3NY8), isoprenaline (2Y03), salbutamol (2Y04), and dobutamine (2Y00). Otherwise, we built ligand-bound receptors by docking the ligands to active and inactive β 2 AR crystal structures using the same protocol as in a previous study [ 38 ]. That is, the binding poses of the ligand were developed using a grid-based MD docking algorithm, CDOCKER [ 39 ].…”

“…The orientations of the prepared structures in the membrane were adjusted according to the Orientations of Proteins in Membranes database, which determines the orientation by minimizing the protein transfer energy with respect to angle variables [ 40 ]. The 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer of 256 molecules was a pre-equilibrated and fully hydrated around GPCR structure [ 38 , 41 ]. The pre-equilibrated membrane was able to accommodate either the R or R* state of β 2 AR with only relatively mild clashes, and they were further relaxed in MD simulations longer than 5 ns.…”