Approaches for Prioritizing High-Quality Chemical Matter in Chemical Probe and Drug Discovery

This special collection in SLAS Discovery showcases approaches to identifying high-quality chemical matter in chemical probe and drug discovery. No one purposefully embarks on a high-throughput screening (HTS) campaign with the intention of selecting low-quality compounds. However, it is common experience in the screening community that the majority of primary hits are unsuitable for further progression. Causes include irreproducible activities (false-positives), nonspecific and poorly optimizable mechanisms of action (reactivity, aggregation, chelation), impurities, poor physicochemical properties, undesired cytotoxicity, and technology interferences (artifacts), to name a few. Yet despite widely available knowledge, considerable resources and prominent scientific publications are still devoted to pursuing low-quality chemical matter. Identifying high-quality chemical matter can be thought of as a two-part process: (1) de-prioritizing chemical matter with certain liabilities (e.g., frequent-hitting behaviors, lack of structure–activity relationships) and (2) prioritizing bioactive compounds with favorable properties (e.g., selectivity, potency, synthetic accessibility, solubility). This special collection topic was chosen to call attention to the scope of this problem and to highlight recent scientific advances to address this problem.

A well-designed screening cascade is essential for efficiently and robustly triaging low-quality chemical matter such as interference compounds. ¹ In a first for SLAS Discovery, Ina Rothenaigner and Kamyar Hadian provide interested readers with a full-page graphic summarizing assay-based triaging strategy workflows to reduce the impact of interference compounds in cell-free and cellular assays. ² This format is based on the popular SnapShot graphical reference guides in Cell. A full-color, high-resolution, printer-friendly graphic is available in the online article for those interested in displaying this useful illustrated reference in their laboratories.

Compound quality is often discussed in terms of metrics such as activity, selectivity, and physicochemical properties. In their Perspective, Kathryn M. Nelson and Michael A. Walters advocate for adopting more standardized reporting of compound natural histories in the scientific literature. ³ Their proposed natural history visualization (NHV) includes metrics for purity/chemical identification, promiscuity (BadApple, Hit Dexter 2.0), physicochemical property scoring (Abbott Physicochemical Tiering), and a literature search (SciFinder). Using literature examples, the authors describe how NHVs can effectively communicate compound quality in a straightforward, systematic approach. The adaptation of NHVs by scientific journals could be another tool to enhance the quality of our literature.

A continued challenge of HTS and high-content screening (HCS) is the resources required for full-deck screening. At many institutions, small-scale compound sets (informer sets) that represent the diversity of a larger collection or a specific set of bioactivities are used to estimate assay performance and library performance and also perform iterative screening. In their Perspective, Clemons and colleagues at the Broad Institute describe their collective experiences with small-molecule informer sets for HTS and HCS, including the use of such a set based on diversity-oriented synthesis (DOS). ⁴ The lessons articulated in this report should be useful for academic and industrial screening groups looking to maximize resources anywhere from assay development to large-scale screens.

There is a growing interest in quantifying compound binding in early-stage discovery and development, including exploiting drug residence times. Using case examples and simulations, Samuel Hoare of Pharmechanics describes the importance of thoroughly understanding compound–target binding kinetics in drug discovery. Cases are described where binding kinetic measurements from the highest-quality chemical matter might be the most affected by “underappreciated infringements” such as ligand depletion and equilibration artifacts. ⁵ Importantly, the author provides several expert recommendations and even simulation tools for addressing these issues.

Readers of this special collection will be more convinced of the problem of low-quality compounds in drug and chemical probe discovery. At the same time, this collection should invoke a sense of optimism in readers. While low-quality chemical matter in screening will almost certainly never go away, applying rigorous scientific methods and harnessing scientific creativity will mitigate this problem and allow our screening community to focus on higher-quality chemical matter with increased chances of downstream success.