GOLD Virtual Screening in Drug Discovery
In the pantheon of virtual screening algorithms, GOLD (Genetic Optimization for Ligand Docking) from the Cambridge Crystallographic Data Centre (CCDC) stands out as a trusted workhorse, whose reputation and reliability has been built and maintained over more than 20 years. It is known for its ability to accurately predict how ligands bind to protein binding sites, helping researchers through the stages of drug discovery from lead identification to lead optimization, to focus on the most promising therapeutic candidates.
At its heart, GOLD uses a genetic algorithm to mimic the process of natural selection, efficiently exploring small molecule conformational space for the best ways a ligand can be oriented in a protein binding site. GOLD can handle both ligand flexibility and account for partial flexibility in the protein target, as well as the displacement of water molecules during the binding process. GOLD offers multiple scoring functions to evaluate binding affinity and pose quality, and these have helped to make it a versatile algorithm, adaptable to a wide range of drug discovery targets.
GOLD and Discovery Studio
The relationship between GOLD and Discovery Studio goes back to 2006 before the company, Accelrys, became part of Dassault Systèmes. The protein preparation tools in Discovery Studio were preferred by many users at that time, and to this day they remain excellent and easy-to-use workflows to automatically prepare protein structures. From correcting problems with experimental crystal structures, missing atoms, sidechains, and loops, to calculating pK and protonation states and identifying and preparing binding sites, many users prefer the Discovery Studio interface and tools. Users also have the option to hand curate each of the aspects of the protein preparation themselves and also include other steps such as molecular dynamics for refining structures. For ligand preparation there are tools for ligand libraries to correct valences, ionization, tautomers and isomers as well as generate 3D coordinates ready for docking.
After docking their ligand libraries with GOLD, users find the plethora of post-docking refinement, analysis and filtering tools in Discovery Studio essential to optimizing the docking results themselves. Users are able to further easily refine docked poses with additional minimization and molecular dynamics. If the numerous scoring functions in GOLD are not sufficient for a user’s target, Discovery Studio provides a wealth of additional literature scoring functions, scoring functions from several other docking algorithms, as well as energy-based functions such as binding energy and interaction energy calculations. In addition, detailed non-bond interactions can be quickly calculated and analyzed for all poses. Altogether this data helps users rank better poses, filter out undesirable interactions and orientations, and discriminate between active and inactive ligands, depending on the particular screening objectives. Depending on what stage of a virtual screening users are working through – testing, validation or final screen – Discovery Studio includes a full suite of tools to maximise the results and value of the GOLD virtual screening.
GOLD on the 3DEXPERIENCE Platform
Today, the BIOVIA-CCDC partnership has been enhanced with GOLD now available on the 3DEXPERIENCE platform and accessible from even more applications. Discovery Studio Simulation is the Software-as-a-Service version of BIOVIA’s life science atomistic modeling and simulation application Discovery Studio. It provides the same ability to run GOLD virtual screening and access to all the supporting tools and workflows just described above. The difference with Discovery Studio Simulation is that all the calculations are running on the Dassault Systèmes high-performance cloud computing 3DEXPERIENCE platform. This means that users no longer have to worry about hardware, installation and IT concerns. The flexibility of shared cloud resources is that it efficiently gives users immediate access to what they need to support different types and scales of drug discovery projects without having to make expensive up-front hardware investments.
GOLD is also available as a virtual screening method in Generative Therapeutics Design (GTD), BIOVIA’s latest small molecule lead generation and optimization application, as well as Insight for Research, an application for medicinal chemists to analyze data. Once a computational chemist has developed a successful docking procedure for a particular target with GOLD and Discovery Studio Simulation, that protein model and docking method can be published and shared with other project team members to their Model Repository, making it accessible to users in GTD and Insight for Research.
GTD is a drug design nexus, a central hub where users can bring together a host of models to be used for the generation of novel small molecule therapeutics optimized against a custom defined Target Product Profile (TPP). These models may include machine-learning models, or 3D pharmacophore or GOLD docking models from Discovery Studio Simulation, or any combination of these to score for a target or for anti-targets. A number of other drug-related property calculators (physico-chemical properties, ADME-toxicity calculations, synthesizability scoring) can also be considered in combination with these models to constitute the custom TPP. GTD generates novel molecules and evaluates them in a multi-objective optimization of the TPP, keeping the best molecules and iteratively repeating this generative process to create optimized small molecule candidates that can be passed to lab chemists to synthesize. Those results are fed back to GTD to retrain the models and refine the profile to quickly improve the next round of molecules generated. Thus, for drug design projects that include a protein target, GOLD can play an invaluable role in accelerating generative ideation of better candidates for the drug discovery team.
These uses of GOLD on the 3DEXPERIENCE platform have been focused on expert users, such as computational chemists, performing virtual screening campaigns or using those docking methods as part of a generative drug design optimization program. However, GOLD is as accessible to non-expert members of the drug discovery team through 3DEXPERIENCE’s Insight for Research application. The same GOLD docking model and method published from Discovery Studio Simulation, that can be used in the generative design cycles in GTD, can also be used by medicinal chemists to test molecular ideas they may want to explore. The published model available in Insight for Research makes the docking as simple as possible for users, and allows them to focus on analyzing the resulting docked ligands and prioritizing the best candidates to progress to the lab.
A virtual screening algorithm as extensively validated and respect as GOLD is an absolute imperative in today’s toolkit of drug design methods to accurately predict molecular interactions and accelerate the identification and optimization of new therapeutics. The combination of GOLD on the 3DEXPERIENCE platform with Discovery Studio Simulation, Generative Therapeutics Design and Insight for Research is very powerful. Together they offer an advanced docking algorithm with a powerful iterative design application and comprehensive virtual screening and interaction analysis tools to help drug discovery teams accelerate their drug development processes and achieve better outcomes.
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Tien Luu is the Product Manager and Principal Scientific Specialist at BIOVIA Dassault Systèmes, managing aspects of life science modeling and simulation predictive science solutions. She began her career as a Scientific Specialist after receiving her Ph.D. in Chemistry from the University of Wollongong, Australia. Since joining BIOVIA 22 years ago, Tien’s passion and excitement for helping customers accelerate their R&D have been steadfast and she is committed to improve customer experiences and product successes. In addition, she continues to be an active leader in scientific software product development, new program initiatives, and new applied and fundamental scientific research.