GOLD: The All In One Molecular Docking Package
A Versatile and Configurable Protein–Ligand Docking Software
Here we present the main features of GOLD, a validated, configurable protein–ligand docking software for expert drug discovery, alongside four case studies that use this versatile tool from the CSD-Discovery suite.
Explore more about GOLD.
What Is GOLD?
GOLD (Genetic Optimisation for Ligand Docking) is a genetic algorithm for docking flexible ligands into protein binding sites.
With GOLD, it is possible to perform pose prediction to validate ligand docking results. It has proven success in virtual screening, lead optimisation, and in identifying the correct binding mode of active molecules.
Key Features
GOLD employs four scoring functions (ChemPLP, ChemScore, GoldScore, and ASP), can deal with key water molecules, and presents several features for dealing with protein flexibility.
It contains several different user-defined constraints, including H-bond, hydrophobic region, scaffold, and similarity constraints.
Python API Access
All the functionalities are available through the Python API, where it is possible to run dockings programmatically for parameter optimization and workflow incorporation.
Discover more about the protein–ligand docking software GOLD.
Using GOLD in Cancer Research
Foiling a Protein–Protein Interaction to Help Fight Cancer
In this work, the team used a drug repurposing approach to search for non-covalent inhibitors effective against chromosome region maintenance 1 (CRM1).
CRM1 is a nuclear export protein that is overexpressed in many cancer types, and is hence an attractive cancer drug target.
The scientists virtually screened a library of marketed drugs to identify potential lead scaffolds for this target. The structures of these drugs were then docked into the CRM1 active site using GOLD.
Zafirlukast (ZAF) was identified as a novel non-covalent and stable CRM1 inhibitor, and displayed in vitro activity against a broad range of cancer types.
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Ovarian Cancer Drug Identified by Virtual Screening
This work reported the use of GOLD to identify a promising ribonucleotide reductase (RNR) inhibiting candidate for the treatment of ovarian cancer.
Triapine, a RNR inhibitor, is known to be effective in the treatment of epithelial ovarian cancer (EOC). Here, the scientists used virtual screening to investigate protein-ligand docking of the triapine-binding pocket on RNR and identify a next generation RNR-inhibiting candidate to treat EOC.
Virtual screening using GOLD of over 200,000 compounds revealed the interactions with the triapine binding pocket. Hit-clustering was performed on the most promising 200 compounds, narrowing the candidate field down to 25 candidates.
Experimental validation and further physicochemical analysis identified a potential candidate.
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Using GOLD: From Herbicides to Organometallics
Structure-Based Drug Design to Develop Novel Herbicides
In this work, the researchers used GOLD to rationalize structural modifications of a new class of p-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors with potential use as herbicides.
HPPD plays a pivotal role in the tyrosine degradation pathway, which, in plants, results in a key enzymatic product important for photosynthesis. Hence, blocking HPPD would disrupt the photosynthesis, leading to the plant’s death.
The team designed a family of new HPPD inhibitors for the development of novel herbicides, and used GOLD to identify their binding modes. From a total of 300 generated conformations, the most promising ones were evaluated with additional computational methods.
Finally, a subset of these were synthesized and their herbicidal effect was demonstrated.
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Investigation of Interactions in Organometallic Compounds
In this work, the scientists used GOLD to investigate the interactions of organometallic complexes of ispinesib, a known kinesin spindle protein (KSP) inhibitor, at the ispinesib-binding site of human KSP.
Antimitotic agents are important drugs in anticancer therapy, but have strong side effects and can lead to resistance. KSP was proposed as a promising target for new antimitotic drugs, and good KSP inhibitory activity was demonstrated in clinical trials when combining ispinesib with metal-based drug candidates, like carboplatin.
Here, the authors prepared organometallic complexes from the R and S-enantiomers of ispinesib with Ruthenium (Ru), Osmium (Os), Rhodium (Rh), Iridium (Ir) as metal centres.
GOLD was then used to compare the docking of the metal complexes at the ispinesib-binding site of human KSP to that of ispinesib (R) and (S)-enantiomers, revealing important interactions with the binding site residues.
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