Moe 2019

The known crystal complexes of HDAC1, HDAC6, HDAC8 and their ligand (PDB code: 5ICN, 5EDU, 4RN0) were obtained from PDB (http://www.rcsb.org). Molecular docking simulations in the HDACs were run using the MOE 2019 (Molecular Operating Environment, Chemical Computing Group, Montreal, Quebec, Canada) due to its universality and very fast speed. Ligands were prepared with the ChemBio3D Ultra 14.0 (PerkinElmer, Waltham, MA, USA), followed by MM2 energy minimization. Protein structures were also prepared with the MOE, which could automatically add hydrogen atoms to proteins by explicitly considering the protonation state of histidine and optimize the force field. All crystal water, small ligands and cofactors except HEM were removed. After this step, the binding sites were deduced from the known crystal complexes and the ligands were docked to the prepared proteins through flexible docking mode. Top scoring function poses were selected as representative of the simulations and were displayed with Open-Source PyMOLTM 1.8X software (Schrödinger, Ltd, New York, NY, USA).

Molecular docking is a computer simulation method to explain the binding patterns and interaction mechanisms between biomolecules at the atomic level. The crystal structure of the ACE receptor protein (1O8A) obtained from the PDB database was used as the target protein. MOE2019 (Chemical Computing Group ULC., Montreal, BC, Canada) was used to optimize the energy and structure of the ACE receptor and construct the 3D structure database of undecapeptides. Combining the critical amino acid residue (ALA354, GLU384, TYR523, GLN281, HIS353, HIS513, LYS511, TYR520, GLU162) in functional pockets (S1, S2, S1′) of the ACE receptor reported in the literature [5 (link)], the docking scoring value, the number of bonds formed, and the docking energy of undecapeptides to the ACE receptor were used as indicators to select the tightly bound undecapeptide–receptor complexes. Molecular docking was performed with 3 replications to verify the stability of the molecular simulation results. The Site Finder computed and applied the docking sites in the ACE receptor. The London dG score and number of poses were defaulted in MOE. MOE analyzed the interaction modes of the undecapeptides and the ACE receptor.

Molecules were drawn with ChemBioDraw Ultra 13.0 software and minimized with MOE 2019 (Chemical Computing Group Inc., Montreal, QC, Canada). The SL receptor OsD14 (PDB: 5DJ5) and ShHTL7 (PDB: 7SNU) downloaded from Protein Data Bank (https://www.rcsborg accessed on 2 April 2023) were prepared by the process of deleting water, adding hydrogen, adding Gasteiger charges, merging nonpolar hydrogen and so on by AutodockTools-1.5.6 (Scripps, La Jolla, CA, USA). Docking was operated by MOE 2019 after setting method (placement: triangle matcher, refinement: rigid receptor), score (placement: London dG, refinement: GBVI/WSA dG) and poses (placement: 300, refinement: 5). The lowest binding energy for the docked conformations was chosen from 300 conformations as the representative binding energy to evaluate the potential of the corresponding compounds. The best docking poses were selected for analyzing the interactions between SL receptor and target compounds.

Molecular docking was performed using the Molecular Operating Environment software (MOE 2019) (Chemical Computing Group, Montreal, Canada). The crystal structure of the CA_CTD-SP1 Gag fragment (PDB ID: 5I4T) was obtained from the RCSB Protein Data Bank. The structure file was subjected to the QuickPrep procedure of MOE. The BVM structure was taken from the PubChem database. The 3D structure of DSC was generated using Chem3D software 2018. Multiple conformations of small molecules in the format of mol2 were generated as ligand libraries using Frog2.14 program (https://bioserv.rpbs.univ-paris-diderot.fr/services/Frog2/, accessed on 7 October 2021). The partial charges of all protein and ligand atoms were calculated using the implemented Amber10: EHT force field. For both ligands, all poses were located inside the cavity formed by the 6HB with different positions or orientations. Docking simulation was carried out choosing the triangle matcher for placement of the ligand in the binding site and ranked with the London dG scoring function. The best 30 poses were passed to refinement and energy minimization using the rigid receptor method and then rescored with the GBVI/WSA dG scoring function.

Modeling, simulations and structural visualizations were performed using MOE 2019 (Chemical Computing Group ULC, Montreal, CA) based on RCSB Protein Data Bank structure 2I66.^{72 (link)} The protein was protonated at T = 310 K, pH 7.0, salt at 200 mM using GB/VI electrostatics. Docking simulations used flexible receptor and flexed the ligand, while docking targeted the active site. For each docking simulation initial placement calculated 50 poses using triangle matching with London dG scoring, the top 5 poses were refined using forcefield Amber10:ETH and Affinity dG scoring (Escore2). The top pose was used then refined using molecular dynamics. Molecular dynamics used the NPA algorithm and the Amber10:ETH forcefield. Solvent was a water droplet with 0.1 M NaCl and used 9518 solvent molecules. Simulation protocol was an equilibrium step for 100 ps at 300 K and a production step for 500 ps at 300 K with a step time of 0.5 ps.