Novel Scaffolds in the CHEMriya Update — Find Favorites with infiniSee 3.3


Novel Scaffolds in the CHEMriya Update — Find Favorites with infiniSee 3.3

January 20, 2022 09:00 CET

Novel scaffolds are one of the driving forces behind modern drug discovery. For a drug to be financially lucrative pharmaceutical companies require exclusivity over the production and distribution rights in the form of a patent. Yet, patents and the connected intellectual property (IP) are only granted to chemically novel drug candidates with unique scaffolds; moreover, patents are constrained by medicinal indication criteria to promote competition and innovation. Easy access to novel scaffolds in the early stages of drug discovery is therefore necessary and beneficial for the drug discovery process as it accelerates SAR studies, allows tuning of ADME properties, and reduces costs and resources.

With the December update of Otava’s make-on-demand Chemical Space CHEMriya over 500 million novel molecules have been added. With a total of seven new reactions and the respective addition of the required building blocks, CHEMriya reaches over 11.8 billion entries for drug discovery and scaffold hopping projects. Compounds of interest can be ordered conveniently from Otava.

Discovering Close Neighbors in Vast Chemical Spaces with infiniSee

An example of an infiniSee search can be found in Figure 1 below. Here, a 4-anilinoquinazoline, a second generation EGFR inhibitor, is taken as the query compound of interest. Based on the structure infiniSee returns results that share molecular features of the query compound. The fuzzy pharmacophore search catches the ‘overall concept’ of the molecules and can be modified according to the needs of the project. In this case the acrylamide was selected as an important molecular feature to keep the Michael acceptor functionality for potential covalent binding of the result compound at the target.

Novel scaffpold discovery of potential eGFR inhibitors Figure 1. An example of an infiniSee search for a 4-anilinoquinazoline compound in CHEMriya. The query molecule was a precursor in the discovery of the FDA approved Afatinib.

infiniSee also delivers visual feedback to the user on why the software “considers” a molecule to be similar to the query compound (see Figure 2 below). The user can now profit from his knowledge and subsequent analysis of the compounds: Are pharmacophore functionalities present in the result compound? Is it chemically diverse (or close enough) to be of interest for the project? Numerical values for the underlying “FTrees” similarity score are provided by the software to allow a closer look and evaluation of certain areas and the molecule pair. Result molecules can also be exported as SMILES for further evaluation by molecular docking studies or other computational approaches.

Novel scaffold similarity depiction
Figure 2. Visual FTrees similarity comparison between the query compound (left) and a compound from the CHEMriya Space (right).

Novel Scaffolds in CHEMriya

Every Chemical Space update features new reactions that further expand the space and contribute to its diversity meaning that not only the number of included molecules increases but the potential of the space as well! One addition of the January 2022 update of CHEMriya is an extended set of unsaturated Michael acceptors as potential covalent binders. Other added scaffolds feature benzimidazoles, triazolopyridines, thiazoles, benzoxazinones and other morpholine derivatives (see Figure 3.)

New reactions may quickly contribute several thousands to millions of novel entries to the space as ammunition for drug discovery projects. A single reaction can therefore easily exceed most target focused or scaffold-based commercial screening libraries by several orders of magnitude.

Figure 3. Selection of novel scaffolds now featured in CHEMriya. Moieties highlighted in blue are products of newly added reactions.

Discovering novel scaffold has never been easier through the combination of the ultra-fast infiniSee and accessible molecules from make-on-demand Chemical Spaces like CHEMriya. Start your Chemical Space discovery with CHEMriya and infiniSee today. Download and test it for free with no strings attached.