Identifying hQC Inhibitors of Alzheimer’s Disease by Effective Customized Pharmacophore-Based Virtual Screening, Molecular Dynamic Simulation, and Binding Free Energy Analysis

Abstract

Human glutaminyl cyclase (hQC) appeared as a promising new target with its inhibitors attracted much attention for the treatment of Alzheimer's disease (AD) in recent years. But so far, only a few compounds have been reported as hQC inhibitors. To find novel and potent hQC inhibitors, a high-specificity ZBG (zinc-binding groups)-based pharmacophore model comprising customized ZBG feature was first generated using HipHop algorithm in Discovery Studio software for screening out hQC inhibitors from the SPECS database. After purification by docking studies and drug-like ADMET properties filters, four potential hit compounds were retrieved. Subsequently, these hit compounds were subjected to 30-ns molecular dynamic (MD) simulations to explore their binding modes at the active side of hQC. MD simulations demonstrated that these hit compounds formed a chelating interaction with the zinc ion, which was consistent with the finding that the electrostatic interaction was the major driving force for binding to hQC confirmed with MMPBSA energy decomposition. Higher binding affinities of these compounds were also verified by the binding free energy calculations comparing with the references. Thus, these identified compounds might be potential hQC candidates and could be used for further investigation.

Influence of the pKa value on the antioxidant activity of licorice flavonoids under solvent‐mediated effects

“…Two‐level equilibrium is achieved by using a constant number of particles, volume, and temperature (NVT) and a constant number of particles, pressure, and temperature (NPT) to stabilize the system. The simulation time is 15 ps, the time step is 65 ps, the initial temperature is 50 K, and the target temperature is 300 K. [ 45 ] The equilibrium phase is carried out at 85 ps and 298 K. After the structure was stabilized, Trajectory analysis was used to analyze the root‐mean‐square deviation (RMSD), potential energy, and hydrogen bond.…”

“…system. The simulation time is 15 ps, the time step is 65 ps, the initial temperature is 50 K, and the target temperature is 300 K. [45] The equilibrium phase is carried out at 85 ps and 298 K. After the structure was stabilized, Trajectory analysis was used to analyze the root-mean-square deviation (RMSD), potential energy, and hydrogen bond.…”

Investigative on the Molecular Mechanism of Licorice Flavonoids Anti-Melanoma by Network Pharmacology, 3D/2D-QSAR, Molecular Docking, and Molecular Dynamics Simulation

“…The system was then balanced by the NVT ensemble (constant number, volume, and temperature of particles) and the NPT set (constant number, pressure, and temperature of particles). Finally, the final protein–ligand complex model of MD simulation was obtained by generating trajectories ( Lin et al, 2019 ).…”

Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation

“…To further observe the stability of the hit compounds in the binding pocket, molecular dynamic simulation of the respective and reference compound was done by using GROMACS-2018 [ 30 ] by employing the GROMACOS9653a6 force field [ 31 , 32 ]. The topologies of the ligand were generated through Antechamber Python Parser interface (ACPYPE) [ 31 , 33 ]. Counter ions were added to neutralize the SPCE water model present in the cubic box.…”