#Molecular scaffold meaning series#

Literature publications have reported the utilization of molecular enumeration methods in designing medicinal chemistry reagents, (14) enhancing de novo and structure-based molecular design (15, 16) and exploring heterocyclic regioisomers (HREMS). To enhance the application of objective scaffold definitions in HTS compound clustering and triaging, it would be beneficial to introduce some controlled fuzziness in the molecular scaffold representation that is structurally relevant and interpretable for synthetic medicinal chemistry. These “singleton” scaffolds may be more challenging for hit confirmation and expansion, (13) and may often be deprioritized when shortlisting screening-hit matter for hit-to-lead activity. Nonetheless, objective scaffold definitions may sometimes be too stringent and result in molecular scaffolds that are only represented by single exemplars without revealing other structural analogs in a screening library.

#Molecular scaffold meaning series#

On the contrary, clustering methods such as molecular fingerprint similarity clustering (11) and HTS fingerprints (12) may cluster together molecules of low structural resemblance to each other, which may hinder the assembly of SAR information when prioritizing compound series and developing medicinal chemistry design strategies. This approach can quickly identify compound clusters with promising screening results that can be prioritized for further hit-to-lead studies.

Screening compounds that share the same molecular scaffold can be clustered together and SAR information can be readily derived. The application of objective scaffold definitions in clustering screening hits represents a structure-oriented approach to understand the SAR of HTS data. The enumerated scaffold clusters generated would constitute a comprehensive collection of scaffolds for scaffold morphing and hopping. EnCore complements literature enumeration methods in enabling changes to the physicochemical properties of molecular scaffolds and structural modifications to aliphatic rings and linkers. A case study using literature cyclooxygenase-2 inhibitors further demonstrates the advantage of EnCore application in establishing SAR from structurally related scaffolds. These results illustrate the potential of EnCore to enrich SAR information. In particular, over 60% of the singleton scaffolds with only one representative compound were found to have structurally related compounds after enumeration. When EnCore was applied to analyze an HTS library containing over 200 000 compounds, we observed that over 70% of the molecular scaffolds matched extant scaffolds within the library after enumeration. Analysis using the top representative Level 1 scaffolds this list of literature compound series demonstrated that EnCore could mimic the scaffold exploration conducted when establishing SAR. A list of 43 literature medicinal chemistry compound series, each containing a minimum of 100 compounds, published in the Journal of Medicinal Chemistry was collated to validate the protocol.

We describe the development of EnCore, a systematic molecular scaffold enumeration protocol using single atom mutations, to enhance the application of objective scaffold definitions and to enrich SAR information from analysis of high-throughput screening output. Establishing structure–activity relationships (SARs) in hit identification during early stage drug discovery is important in accelerating hit confirmation and expansion.