There is a recurring trend in modern drug discovery that involves looking at natural products (NPs) as a source of inspiration in the design of screening libraries. However, difficulties with follow-up optimization chemistry may occur after the initial screen as NPs tend to be rather complex.
An important issue is the IP position of the scaffold. Unfortunately, the need to achieve composition-of-matter patent status can be misguided as it can lead research groups away from the biologically active chemical space. Therefore, when studying NPs as a source of inspiration and diversity, it is wise to only consider NPs that have proven to be target specific.
In the past, compound collections were designed according to drug-like criteria that addressed oral bioavailability issues rather than binding capabilities. But does this rule help medicinal chemists develop a molecule with predesigned activity and amenability for follow-up optimization?
Current trends have dictated that the criteria for high-quality compound libraries has switched from drug-like to lead-like. This means that medicinal chemists favor compounds enriched with pharmacophore elements but with stricter physical chemical properties (preferably measured rather than calculated). Most of all, medicinal chemists like chemically flexible scaffolds that allow the exploration of different synthetic directions during the hit-to-lead phase.
To further explore these trends in compound library design, scientists at Asinex performed a comparative analysis of NPs with annotated biological target activity, known drugs, and publicly accessible compound collections.
Significant discrepancies emerged during the comparison of the molecular structures of these three datasets. It was found that saturated ring systems such as fused, spiro, and bridged molecules—which are intrinsically rigid and not flat—together with oxygen-enriched molecules are common features of NPs and conversely are poorly represented in commercial compound libraries.
In order to translate the results of statistical analysis into practical chemical ideas, we selected frameworks that are frequently found in NPs but are underrepresented among publicly available screening collections, limiting the number of rings to three. This limitation is advisable since more complex systems would direct us away from lead-likeness. These frames have been populated with O and N atoms in a judicial way in order to obtain a core with desirable pharmacophore elements, novelty, and feasibility (Figure 1).