Computational protocol: Investigation of the Structure Requirement for 5-HT6 Binding Affinity of Arylsulfonyl Derivatives: A Computational Study

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Protocol publication

[…] When the experimental 3D-structure of the protein is not available, homology modeling is a powerful tool with homologous proteins whose 3D structures are known. In the present study, due to the unavailability of human 5-HT6 3D-structures, homology modeling process was employed to predict the protein structure from the target amino acid sequence obtained from the National Center for Biotechnology Information database []. The homology model of 5-HT6 was built in Automated Mode and the amino acid sequence of 5-HT6 was submitted to SWISS-MODEL server []. The template protein (PDB code: 2RH1 chain A, obtained from the Protein Data Bank [], a high resolution (2.4 Å) crystal structure of human β2-adrenergic G protein-coupled receptor [], was employed to generate the 3D protein structure. [...] The MD simulations were performed with GROMACS software package [] using the GROMOS96 force field []. The molecular topology file for the ligand in protein was generated by the program PRODRG 2.5 [,]. The simulation cell was a cubic periodic box with a side length of 112.52 Å, and the minimum distance between the protein and box walls was set to larger than 10 Å. Herein, in order to neutralize the total charge, 17 chloridions were placed randomly in the box. The total number of the atoms of the simulation system was 138230 including the protein complexes and waters. The remaining box volume was filled using the simple point charge (SPC) water []. Prior to the simulation, an energy minimization was applied to the full system without constraints using the steepest descent integrator for 8854 steps, then the system was equilibrated via a 200 ps MD simulation at 300 K. Finally, a 5 ns simulation was performed with a time step of 2 fs. During MD simulation, the standard parameters and main calculation methods were set as follows: The model used NPT ensemble at 300 K with periodic boundary conditions, the temperature was kept constant by the Berendsen thermostat, the value of the isothermal compressibility was set to 4.5 × 10−5 bar−1 while the pressure was maintained at 1 bar using the Parrinello-Rahman scheme [], the electrostatic interactions were calculated using the particle mesh Ewald method [,], the cut-off distances for the calculation of Coulomb and van der Waals interactions were 1.0 and 1.4 nm, respectively. All the MD simulations lasted 5 ns to ensure that the whole systems were stable. […]

Pipeline specifications

Software tools SWISS-MODEL, GROMACS, PRODRG
Applications Drug design, Protein structure analysis
Chemicals Hydrogen, Serotonin