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CHARMM-GUI Covalent Ligand Docker as a Web-based Molecular Docking Platform for Covalent Ligands
Lingyang Kong1, Donghyuk Suh1, Wonpil Im1
1Departments of Biological Sciences, Lehigh University, Bethlehem, PA 18015, USA.
Biorxiv : the Preprint Server for Biology
|July 29, 2026
Summary
Researchers developed CHARMM-GUI Covalent Ligand Docker (CGUI-CLD) to simplify covalent ligand docking. This tool automates complex preparation and simulation, accelerating drug discovery research for covalent inhibitors.
Area of Science:
- Drug Discovery
- Computational Chemistry
- Structural Biology
Background:
- Covalent inhibitors offer enhanced specificity and efficacy in drug discovery.
- Molecular docking is crucial for predicting ligand-receptor interactions but challenging for covalent ligands due to structural changes.
- Existing methods require extensive manual preparation for covalent docking simulations.
Purpose of the Study:
- To develop an automated computational tool for facilitating covalent ligand docking.
- To streamline the preparation and simulation workflow for covalent inhibitor drug discovery.
- To enhance the accessibility and efficiency of covalent docking studies.
Main Methods:
- Development of CHARMM-GUI Covalent Ligand Docker (CGUI-CLD) module integrated with AutoDock4.
- Implementation of automated ligand preparation, modification, and docking simulation functionalities.
- Creation of a knowledge-based library supporting 66 warheads and 8 amino acids for reaction adduct transformation.
- Integration with CHARMM-GUI High-Throughput Simulator for rapid system generation.
Main Results:
- CGUI-CLD automates the transformation of ligands from pre-reaction to post-reaction states.
- The tool provides an intuitive interface for docking simulation and results presentation.
- Seamless integration of covalent reaction simulation within the docking workflow.
- Facilitation of rapid generation of molecular dynamics simulation systems.
Conclusions:
- CGUI-CLD significantly reduces the workload associated with covalent ligand docking.
- The developed module is expected to accelerate research in the field of covalent inhibitors.
- This tool enhances the efficiency and applicability of computational methods in drug discovery.
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