Computational protocol: A new serotonin 5-HT6 receptor antagonist with procognitive activity – Importance of a halogen bond interaction to stabilize the binding

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Protocol publication

[…] MODELLER v9.12 was used to build a homology model of human 5-HT6R (Uniprot code P50406) (one hundred molecular models were generated) using the three-dimensional crystal structure of the 5-HT2BR (PDB code 4IB4) as template. Sequences were aligned using the highly conserved residues shared within the GPCR family (see ). Loops regions were optimized through a MD Simulated Annealing protocol. For this purpose, backbone residues of TMs and Helix 8 were constrained and the conformation of loops were optimized in 20 Simulated Annealing cycles of heating up to 700 K and slowly cooling down to 300 K in successive 10 K, 100 ps steps followed by an energy minimization. Compounds 7, 10 and 18 were docked into the receptor model using the AutoDock Vina tool. All docking solutions were visually inspected and the poses in which the protonated amine forms an ionic interaction with D1063.32 and the NHSO2 group hydrogen bonds N2886.55 were energy minimized. The binding modes of compounds 7 and 18 to the 5-HT6R were further studied in explicit membrane MD simulations with the GROMACS v4.5.3 simulation package (see ). Molecular systems were subjected to 50 ns of equilibration, with positional restraints on the backbone atoms of the receptor. These restraints were released, and 1 μs MD trajectory was produced at constant pressure and temperature, using the particle mesh Ewald method to evaluate electrostatic interactions. The AMBER99SB-ILDN force field was used for the protein, Berger parameters for the lipids, and the general Amber force field (GAFF) and HF/6–31 G*-derived RESP atomic charges for the ligand. This procedure has been previously validated. The chlorine atom of compound 7 was parameterized according to the positive-extra-point approach proposed by Ibrahim. As a result, two point charges separated by 1.9 Å (a negative charge [−0.0725e] centered on the halogen atom to reproduce the electronegative crown, and a positive charge [+0.04e] centered on a dummy atom on the hind side of the C−Cl bond axis in order to reproduce the positively-charged σ-hole) were used to account for the potential effect of halogen bonding in the standard force field. […]

Pipeline specifications

Software tools AutoDock Vina, GROMACS
Application Protein interaction analysis
Diseases Alzheimer Disease
Chemicals Chlorine, Serotonin