Complex and structurally diverse: the next generation of small molecules

Small molecule drug discovery programmes often use commercial or proprietary compound libraries: a broad collection of molecules that are built by combining a wide variety of synthetically tractable building blocks. With such an extensive array of combinatorial possibilities, libraries can contain millions of compounds that can be screened against a biological target. It has been expected that high-throughput screening (HTS) of small-molecule libraries against a given biological target would identify a significant number of molecules of interest, providing a continuous pipeline of hits that would transition to drugs. Yet this expectation hasn’t materialised, and the pharmaceutical industry finds itself in a productivity crisis with a relatively low return over investment on R&D budgets (1). Despite these, screening campaigns have demonstrated to provide active hits, the main challenge remains in identifying high-quality and viable small molecule candidates that will successfully progress through clinical trials.

“Looking at successful clinical molecules can provide clues on what attributes may improve the ratio of compounds that reach the clinic and eventually benefit patients”

Current libraries have deficiencies despite their ever-growing size (2). The consensus is that the compounds are too similar and that library diversity (in terms of molecular structure and function) is more important than library size (2). Since the overall shape of a small molecule is a key attribute influencing its biological effect (2), it is worth noting that most molecules derived from these libraries are flat, two-dimensional, and architecturally simple, as most of the HTS assays are enriched with flat compounds (3).

Looking at successful clinical molecules can provide clues on what attributes may improve the ratio of compounds that reach the clinic and eventually benefit patients. Many successful molecules are of natural origin, which tend to have 3-dimensional structures and higher complexity (2, 3, 4, 5). There is a need for structurally diverse and structurally complex molecules (6), importantly those that can be readily synthesised.

Complexity matters

Lactic acid ball model. Lactic acid is a chiral compound with a chiral center. File:L-Lactic acid molecule ball.png by Jynto CC0 1.0.

Natural compounds have higher complexity (2,3,4,5). Lovering et al. proposed in 2009 two attributes to measure complexity: the presence of chiral centers and Fsp³ (the fraction of saturated carbons within a molecule) (5).

Chiral carbons are common features of natural products and are associated with more effective and selective binding to target proteins (3). The presence of chiral carbons opens chemical space, obtaining novel molecules with enhanced tridimensionality (3), which can mimic natural compounds. It also increases potency and selectivity (3) which are highly sought-after attributes for molecules to be developed into medicines. Besides other advantages, higher Fsp³ is associated with improved metabolic stability and solubility, and has no significant impact on molecular weight (5).

Overall, molecules that are complex also have been shown to have reduced promiscuity (5), defined here as number of targets inhibited in relation to the number of targets tested in an assay, making them a more specific match for the intended target. Typically, this translates into decreased secondary effects, as well as reduced toxicity (4), which is of utmost importance when considering patient benefits.

The case for diversity

Structural diversity influences a molecule’s biological effect (2) and is a critical aspect to take into account when designing novel molecules. Structural diversity has been usually discussed in terms of building-block diversity, variation in functional groups present, variations in the orientation (stereochemistry) of potential macromolecule-interacting elements and presence of many distinct molecular skeletons or scaffold diversity (2). While scaffold variation has been considered crucial (6,7), variation in all of these elements contribute to molecule shape and thus to biological effects, increasing the ability to discover a novel molecule with unique and clinically relevant effects.

The next generation of small molecules

Besides improving target validation, designing drugs in a way that lowers late-stage attrition could be one of the most important factors to bring new medicines to patients (1). Hunting for structurally diverse and complex molecules leads to interrogation of large areas of chemical space, perhaps even those previously unexplored, which may contain molecules with singular properties rarely seen before (7).

More importantly, it opens a promising future for therapeutic areas in acute need of new therapies.


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  3. Talele, T. Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon. Journal of Medicinal Chemistry 2020 63 (22), 13291-13315 DOI: 10.1021/acs.jmedchem.0c00829
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  5. Lovering, F. et al. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752–6756 DOI: 10.1021/jm901241e
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