SMM Screening

Drug discovery researchers are increasingly turning to novel small-molecule microarrays (SMM) for high-throughput screening of drugs capable of binding targets often referred to as “undruggable.” SMMs could offer an alternative discovery platform to more traditional techniques – especially for newer targets, such as structured RNA. The speed and flexibility of the SMM approach allows it to be informed by and feed into sophisticated machine learning and AI-based algorithms, which are increasingly being used to revolutionize the drug discovery landscape.

Adam Buckle joined Arrayjet in 2017, managing CRO and CMO functions before becoming Chief Scientific Officer in 2023. In this role, he is responsible for the company’s scientific strategy, which includes identifying and addressing the key needs of the scientific market. Small molecule drug discovery players often need help sourcing compound libraries for screening, so Buckle devised a partnership with Chemspace to offer content access as part of Arrayjet’s growing SMM services. 

Here, we speak with Buckle and Chemspace CEO Yurii Moroz.

What are the major trends in the small molecule space right now?
 

AB: I’d highlight three key trends. First, more groups are using small molecules to target structured RNA, which was previously considered “undruggable.” Second, there is a focus on bifunctional small molecule drugs for targeted protein degradation (for example, PROTAC). And third, there is high interest and activity around developing and training AI models for data-driven drug discovery.

YM: Another major trend is shortening the DMTA (design, make, test, and analyze) cycle. Virtual screening and AI-based tools can help with this, but both require experimental data to deliver high-value results. SMMs are capable of delivering this experimental platform.

How does SMM technology work?
 

AB: A SMM can be thought of as a biochemical microchip that functions as an efficient drug discovery screen. To make one, we print thousands of compounds as individual spots in a microscopic 2D grid. 

By testing one SMM “biochip” against a drug target, whole libraries of compounds can be evaluated simultaneously for therapeutic target binding against the microscopic grid of surface presented compounds. Individual compounds that bind the drug target can be moved forward for further development.

The power of the technology lies in its ability to process hundreds of thousands of binding reactions rapidly and reliably, as well as its flexibility to adapt to the individual needs of the user or the therapeutic target type that is being screened. 

YM: Delivering results fast is very important for drug discovery. SMM screens, when coupled with quick compound re-supply and efficient follow-up studies, could help advance and accelerate discovery projects.

What’s the history behind SMM technology? 
 

AB: Early microarray technology in the late 1980s and early 1990s focused on spotting DNA fragments to investigate gene expression patterns. Small molecule microarray technology gained significant traction in the early 2000s. Researchers recognized that the methodologies employed in DNA arrays could be adapted to immobilize small molecules on surfaces, which enables rapid and systematic screening of small molecule interactions with diverse biomolecules.

However, a key challenge was capturing compounds on the array surface. A variety of methods were tested, but most required specific reactive groups to be introduced during compound synthesis. When the Koehler group pioneered the isocynate reactive surface for SMM in 2006, they opened the way forward for a wide spectrum of nucleophilic residues, (common in small molecule libraries) to be captured more easily. Isocyanate surface chemistry persists as the preferred choice for SMM immobilization.

SMM technology has been further refined for maximum compound immobilization by several groups, including the Schneekloth Lab at the National Cancer Institute and the Fei Lab at Fudan University. Key advances include improved spotting technology for higher density and throughput, and improved methods for imaging, detection, and analysis. The quality, diversity, and annotation of compound libraries has also expanded significantly, further enhancing the efficacy of SMM technology.

The miniaturized nature of SMM uses very low compound volumes and low target volumes, which allows very large libraries to be rapidly screened against a large panel of targets, while maintaining low reagent usage costs. Furthermore, the large data sets generated from microarray experiments provide valuable insights into compound interactions, enabling more informed decisions in drug development that can be fed into sophisticated computational models.

SMMs can also be used to generate and test large curated libraries of compounds, facilitating the exploration of the vast chemical space for potential drug candidates. 

What are the most important criteria when choosing SMM technology or an appropriate partner?
 

AB: Choose an SMM screening technology with the quality and throughput to meet commercial demands. It’s also important to choose a team with experience working with SMM. Most importantly, innovation is key; the technology is developing fast, so it’s important to choose a partner who collaborates with others at the forefront of the field. 

How can the small molecule sector remain innovative? 
 

YM: The chemical space is vast! It is estimated to be 10^62 molecules, but the industry is only exploring a very tiny sector of the space of about 10^15 - 10^20 accessible molecules. Though recent advances in screening techniques have presented new ways to explore the space, we still need more reliable approaches to get synthesizable molecules. The industry has been working hard in this direction, but there is still a lot to do.