The Client

Amidst all the advances in scientific understanding and new and increasingly powerful cheminformatics tools and techniques, the perennial question challenging medicinal chemists is “What compound shall I make next?”

Our client is a renowned German pharmaceutical company, focused on human pharma, animal health and biopharmaceutical contract manufacturing with multiple R&D sites worldwide.

The client addresses the pressing what-to-make-next question with a team science approach including medicinal chemistry groups, medicinal chemistry technologies, computational chemistry, and structural research. The simply posed question is difficult to answer because it involves exploring the huge drug-like chemical space, optimizing multiple observed and predicted parameters, and efficiently analyzing and managing massive volumes of disparate data, hypotheses, and workflows. The client wanted to equip its molecular design team with the best digital workflow support tool that could enable rapid and science-driven generation, exploration, selection, and prioritization of potentially promising compounds for synthesis.

Working with Chemaxon during 2018 – 2019, the client co-developed Design Hub, and it is now deployed and used as a central tool by all its compound design teams.

The Solution

Design Hub emerged from a series of joint client-Chemaxon workshops, discussions, and interviews. A major requirement was to combine all the important compound design and selection tools, techniques, and approaches into a single interactive platform that connects scientific rationale, compound design, and computational resources. These include:

Hypothesis-driven Drug Design

to ensure rational approaches are being used in the design and prioritization of new molecules.

Project Overviews

to provide immediate project insights via tools like Kanban Boards on the status, progress, and potential hold-ups of compounds for synthesis and testing.

Ideas

to capture and potentially reuse compound structure ideas and potential modifications so that no good ideas or insight is lost and can be retrieved, reviewed, and repurposed as needed.

Data Integration and Prediction

as its name suggests, Design Hub is a central nexus that links multiple data sources and tools required in drug design:

• Predictive Models: based on internal data including DMPK, CMC, and safety predictions.
• Internal and External Data Sources: links to systems such as the corporate compound registry, chemical inventory, and commercially available chemicals avoid rework by ensuring that proposed compounds are novel, starting materials are available, and required reactants are purchased rather than made in-house.
• Data-driven Recommendations: these enable users to set up optimization parameters that then provide real-time structural modification suggestions based on previous observations and predicted data values.
• 3D Modelling and Docking: links to systems to explore ligand shapes and docking can be accessed from within Design Hub.
• Safety Alerts: these are based on the presence of structural elements that have undesired properties such as high reactivity or metabolic lability.

The client’s multidisciplinary compound design teams can also access and use Design Hub in purpose-built design rooms.

These are equipped with touch-enabled large screens or interactive whiteboards with immediate access to all the applications and data sources discussed above. This collaborative environment supports not only prioritization, but work that you would do at your desk - including de novo design, searches, enumerations, property predictions etc. Your new structures can then be characterized and assessed based on synthetic feasibility, predictive models for 3D-protein interactions, and physicochemical and ADMET properties, as well as novelty searches in literature and commercial databases.

Design Hub in Use

The client’s teams use Design Hub for multiple purposes associated with compound design, and a usage survey of designers showed the following very encouraging levels of uptake, with 97% of the respondents using the first four Design Hub activities below frequently or occasionally:

1. Designing new compounds
2. Reviewing and prioritizing new ideas in design meetings
3. Editing or contributing a hypothesis/design set created by others
4. Sharing designs with team members
5. Tracking the status of compounds from design to registration
6. Synthesis planning and communication with the laboratory

The client also drilled into how individual design teams use Design Hub, comparing their diverse workflows, including organization, meeting preparation, in-meeting, and post-meeting activities. Some teams are open to creating any new hypotheses or design sets, while others limit the number of hypotheses to those based on structural classes or key recurring topics. Another difference was in the handling of links to synthesis planning, where one team transcribed compounds for later discussion, while the other saved the synthesis plans directly in the design set editor in Design Hub and assigned them to lab scientists.

This deeper dive provided several key learnings and pointers to possible platform extensions and enhancements:

• Support for live sessions is critical (e.g., presentation mode, multiple tabs, performance).
• An archiving system would be useful to handle the backlog of Ready for review compounds.
• The ability to organize and retain the many hypotheses and design sets and their overviews is key.
• Better integration of synthesis planning and lab scientists into daily workflows to avoid time-consuming and error-prone transcription steps would help. Alternatively, including the synthesis plans in design sets provides high transparency to the whole team. The caveat here is that the current design set editor is seen to have limited functionality for synthesis planning.

Flexibility to Add Modules and Expand Capabilities

The client values the ability to add custom modules to Design Hub, and cited Structural Alerts as a smart assistant that notifies designers in real time that a proposed structure contains a potentially problematic substructure. Others have been deployed, with more to come.

Longer term, the client sees Design Hub as a central tool integrated seamlessly into its digital landscape, and an important part of its best-of-breed strategy. Several interfaces are already established, such as integration with Certara D360 platform, a connection to the compound management system to find and order building blocks, and a smart assistant that makes real-time recommendations from an internal data-driven tool.

Further planned Design Hub connections include the ability to send compounds to an automated retrosynthetic tool, and to a CRO synthesis management tool and receive status updates; and integration with the client’s electronic lab notebook system.

Most significant updates delivered since project start

• To keep the workspaces organized and clear, we introduced the Archive which lets users remove synthesized or canceled compound ideas from the kanban boards, and we generally upgraded the kanban board with customization options to allow focusing on just parts of the workflow or parts of the overall tasks in the project,
• To speed up use of the application and make the user interface more personal, we introduced view templates across the application that let users save and reuse their preferred calculations, or layout arrangements across projects or different contexts in the same project,
• To easily connect colleagues who need assistance with tasks and ensure team members are up to date, we introduced the ability to notify users in compound commenting by @mentioning and the use of in-app notifications,
• To make the prioritization and selection of the ideal candidate easier, we have introduced the ability to use multiple reference compounds in a design set, and we introduced interactive visualization of complex prediction results, such as docking / binding pose prediction available in spreadsheet views,
• To make the integration into new homegrown solutions easier and take advantage of the vast collection of virtual compounds in Design Hub’s database, we greatly expanded the REST API of the application.

Summary

In summary, facilitating a collaborative and integrated approach, Design Hub empowers scientists with a comprehensive suite of tools, enabling hypothesis-driven drug design, seamless data integration, predictive modeling, and synthesis planning. The platform's flexibility ensures its alignment with evolving research needs and organizational goals. As highlighted by our client's success story, Design Hub not only streamlines workflows but also fosters informed decision-making.