Applied Biochemistry and Biotechnology

, Volume 187, Issue 4, pp 1173–1192 | Cite as

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

  • Weicong Lin
  • Xiaojie Zheng
  • Danqing Fang
  • Shengfu Zhou
  • Wenjuan WuEmail author
  • Kangcheng Zheng


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.


hQC Pharmacophore Molecular docking ADMET Molecular dynamics simulations Binding free energy 


Funding information

This research received supports from the Science and Technology planning Project of Guangzhou (No. 2013J4100071) and the computation environment support by College of Pharmacy, SunYat-Sen University for Discovery Studio 2.5.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


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Authors and Affiliations

  1. 1.Department of Physical Chemistry, College of PharmacyGuangdong Pharmaceutical UniversityGuangzhouChina
  2. 2.Department of Cardiothoracic SurgeryAffiliated Second Hospital of Guangzhou Medical UniversityGuangzhouChina
  3. 3.School of Chemistry and Chemical EngineeringSun Yat-Sen UniversityGuangzhouChina

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