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Updated: Dec 18, 2025
Author Spotlight: Streamlining Protein Target Prediction and Validation via Molecular Docking and CETSA
Published on: February 23, 2024
High-Throughput Docking and Molecular Dynamics Simulations towards the Identification of Potential Inhibitors against
Dongfang Xu1, Guangpu Xue2, Bangya Peng3
1Library of Zunyi Medical University, China.
Abstract:
Human coagulation factor XIIa (FXIIa) is a trypsin-like serine protease that is involved in pathologic thrombosis. As a potential target for designing safe anticoagulants, FXIIa has received a great deal of interest in recent years. In the present study, we employed virtual high-throughput screening of 500,064 compounds within Enamine database to acquire the most potential inhibitors of FXIIa. Subsequently, 18 compounds with significant binding energy (from -65.195 to -15.726 kcal/mol) were selected, and their ADMET properties were predicted to select representative inhibitors. Three compounds (Z1225120358, Z432246974, and Z146790068) exhibited excellent binding affinity and druggability. MD simulation for FXIIa-ligand complexes was carried out to reveal the stability and inhibition mechanism of these three compounds. Through the inhibition of activated factor XIIa assay, we tested the activity of five compounds Z1225120358, Z432246974, Z45287215, Z30974175, and Z146790068, with pIC50 values of 9.3∗10-7, 3.0∗10-5, 7.8∗10-7, 8.7∗10-7, and 1.3∗10-6 M, respectively; the AMDET properties of Z45287215 and Z30974175 show not well but have better inhibition activity. We also found that compounds Z1225120358, Z45287215, Z30974175, and Z146790068 could be more inhibition of FXIIa than Z432246974. Collectively, compounds Z1225120358, Z45287215, Z30974175, and Z146790068 were anticipated to be promising drug candidates for inhibition of FXIIa.
Insights
Researchers identified potent inhibitors of human coagulation factor XIIa (FXIIa), a key target for antithrombotic drugs. Virtual screening and experimental assays pinpointed promising drug candidates for treating thrombosis.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Human coagulation factor XIIa (FXIIa) is implicated in pathological thrombosis.
- FXIIa is a significant target for developing novel anticoagulant therapies.
Purpose of the Study:
- To identify potential FXIIa inhibitors using virtual screening.
- To evaluate the binding affinity, druggability, and inhibition mechanisms of identified compounds.
Main Methods:
- Virtual high-throughput screening of over 500,000 compounds.
- In silico prediction of ADMET properties and molecular dynamics simulations.
- In vitro FXIIa inhibition assays to determine pIC50 values.
Main Results:
- Identified 18 compounds with significant binding energy to FXIIa.
- Three compounds (Z1225120358, Z432246974, Z146790068) showed excellent binding affinity and druggability.
- Compounds Z1225120358, Z45287215, Z30974175, and Z146790068 demonstrated strong FXIIa inhibition activity.
Conclusions:
- Compounds Z1225120358, Z45287215, Z30974175, and Z146790068 are promising candidates for FXIIa-targeted anticoagulant drug development.
- Further investigation is warranted to optimize these compounds for therapeutic applications.
