High-throughput screening remains one of the most powerful, unbiased approaches in drug discovery for revealing small molecule modulators of biochemical and cellular activities. Compound libraries, featuring hundreds of thousands to millions of small molecules, play a critical role in initiating a successful drug discovery program. While pharmaceutical and select larger biotech companies often have their own libraries, many biotech companies rely on partners and contract research organizations (CROs) to access a small molecule library, and in many cases to also perform the high-throughput screen.

Here we discuss four important aspects to consider when selecting a small molecule library for your next high-throughput screening project:

  1. Physiochemical properties: There are different viewpoints on which properties are most likely to translate to successful drug candidates. Lipinski’s “Rule of 5” (molecular weight < 500 Da, < 5 H-bond donors, cLogP < 5) have become more like guidelines rather than rules as criteria for drug-like properties beyond these parameters continues to expand. Therefore, focus on whether pan-assay interfering compounds (PAINS) are excluded from the library and consider the target of interest (will your compound need to cross the blood-brain barrier?). A diverse library is a great option for companies that ultimately will screen multiple targets and diverse activities.
  2. Purity: Confirming hits from a primary screen validates the robustness and reproducibility of the assay and is a reflection on the purity of the compounds in the screening library. Ensuring libraries are > 90% pure and that the libraries are well maintained will assist in achieving higher confirmation rates and accelerating drug discovery programs. Another often overlooked component to consider is the quality and purity of the DMSO (the solvent used to solubilize the majority of small molecule libraries), which can influence enzyme activity and ultimately the success of the screen.
  3. Intellectual property: Identifying a lead compound is a major milestone in drug discovery. Having the freedom to pursue that lead compound is critical. It is important when evaluating small molecule libraries that you have the rights to pursue any hits without restrictions.
  4. Assay compatibility: Accessing a small molecule library is half the challenge, the second is choosing the right assay methodology for screening that library. Consider whether the library is or can be plated in 384 or 1536 format to match the assay needs. Popular assay approaches often rely on fluorescent or optical readouts, and thus generate high-rates of false positive hits due to optical interference from library compounds. To overcome this limitation, label-free methodologies offer an alternative avenue and may enable reaching milestones faster with higher confidence.