AI-Powered Building Blocks “ReadiBLOX” for DEL Synthesis
Drug Hunter recently wrote the article “Decoding DNA-Encoded Libraries for Drug Discovery.” Over the past two decades, DEL technology has evolved to a broadly used hit identification platform in drug discovery. Compared to other approaches like high-throughput screening (HTS), which on average costs $0.4-2 billion to generate a 1-million compound screening collection, an 800-million compound DEL screen library costs less than $1 million. The value of DEL screening speaks for itself.
A robust screen not only relies on the design and execution of the selection experiments (which we discussed in this webinar) but also the quality and diversity of the building blocks (BBs) used to construct DEL. Because the reaction conditions during DEL synthesis must be compatible with DNA, it poses limitations on the types of BBs that could be used in making DEL. Although several vendors (e.g., Enamine, Millipore Sigma) manufacture BBs, there is still a perceived shortage of diverse and novel BBs on the market.
In our previous blog, we described how we leverage AI to design and validate BBs. We use an iterative active learning loop consisting of experimental validation in the lab to generate data and ML models trained on the data to predict the validation outcomes of a new set of BBs. Then, we experimentally validate the predictions and optimize the ML models. The outcome: saving weeks of time for library development.
Drug-Like Features of X-Chem’s BBs “ReadiBLOX”
With AI facilitating the validation of BB reactivity, we’ve synthesized more than 1,000 novel BBs, 700 of which are available to purchase. We show a fraction below while more information is here.
All BBs are synthesized with these considerations:
- Low aromaticity and high fsp3 character which correlates with increased three-dimensionality, allowing more complex 3D structures and better target specificity; in addition, most compounds with high fsp3 characters present improved solubility, lipophilicity profiles, higher developability and enhanced metabolic stability
- Extended chemical space as shown below, where our designs (right panel, pink dots) cover new chemical space compared to existing XBBs on the market (left panel, grey dots). We also include bi- and tri-functional unnatural amino acids (heterocycles condensed with or connected to hetaryl/spiro rings via C-C, C-N bonds or C-O bonds), halo-acids, protected amino acids and halo-amino-acids
- Novelty and innovation are guaranteed as we check against eMolecules and our internal database to ensure that all BBs designed have not been synthesized before
Future of Drug Discovery Enhanced by DEL Technology and AI-Validated Building Blocks
The integration of AI-driven approaches in building block design, coupled with the advancements in DEL technology, marks a significant leap forward in drug discovery. By addressing the critical need for diverse and novel building blocks, companies like X-Chem are paving the way for more efficient and effective hit identification. As this technology continues to evolve, we can anticipate a broader range of drug candidates, faster discovery time lines and potentially lower costs in the pharmaceutical development process. The future of drug discovery looks promising, with DEL technology and AI-designed building blocks playing pivotal roles in unlocking new therapeutic possibilities and potentially bringing life-changing treatments to patients more rapidly than ever before. Contact us today to discuss your BB needs.
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