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New Chemical Entities

New Chemical Entities (NCEs) and Their Discovery

New chemical entities are among the most sought-after type of molecules in both the pharmaceutical industry and academia.
They contain moieties that have not yet been reported in approved drugs or in candidates that have entered clinical trials. This makes them the first potential members of a new class of active substances for therapeutic usage.

Innovation is often accompanied by significant financial interest when these candidates receive approval and are marketed. This makes new chemical entities the hopeful prospects in most discovery campaigns and the ultimate goal to be achieved in the R&D process.

There are numerous 2D and 3D computational methods that can be used to facilitate the discovery of new chemical entities. On this page, we discuss how BioSolveIT can be utilized for this purpose.

Structure-Based Methods

The simplest and most conventional way to discover new chemical entities is through high-throughput screening (HTS) of compound libraries. However, since this process can be very costly and labor-intensive on a large scale, virtual screening (VS) is typically used beforehand in most projects to make a smaller selection of compounds based on predictions, which are then tested.

In this process, virtual molecule sets are docked into the binding pocket of the target and examined for their interactions. Molecules that fit well into the binding pocket and can form high-quality interactions survive the process and make it to the higher ranks for selection.

Virtual screening is important for the discovery of new chemical entities because it treats ligands in an agnostic manner, evaluating only how well something fits into a binding pocket, regardless of how similar the structure may be to known binders. This allows for the emergence of many new chemotypes and molecule classes from a virtual screening run.
BioSolveIT software for docking:
  • SeeSAR: Visual, drug design dashboard for computational and medicinal chemists.
    The external Docking Mode performs the calculations on separate hardware and loads the results back into SeeSAR once they have finished. This enables the convenient and efficient processing of even large molecule libraries as in high-performance computing.
    The external Docking Mode is supported by the scalable virtual screening workflow environment HPSee that enables seamless processing of several campaigns in sequence.
  • Chemical Space Docking™: (as SeeSAR's Space Docking Mode)
    C-S-D is a the next generation of structure-based virtual screening. In this innovative approach, ultra-vast Chemical Spaces, containing billions or even trillions of entries can be screened for the promising candidates to bind at the target structure.
    C-S-D has demonstrated its capabilities to retrieve novel chemotypes for already investigated targets in several campaigns.[1],[2] Furthermore, users can benefit from the parameterization within the software to achieve even better results and access commercially available compounds.
Command-line tools for docking:
  • FlexX: Docking algorithm.
  • HYDE: De-solvation-aware scoring algorithm.

Scaffold Hopping: Same, Same, but Different

Another method to discover new chemotypes and new chemical entities is by using already known binders that already display biological activity on a desired target. The process is similar to the discovery of new scaffolds: starting from one or more template molecules, those are sought that exhibit a similar arrangement of functionalities and thus possess a similar pharmacophore.

The twist to enable this method is to introduce a new degree of freedom or some fuzziness to the matching of the molecules to enable retrieval of somewhat similar yet not completely identical compounds.
One approach is to break down individual parts of the molecule into parameters that reflect the properties of the fragments, followed by the search for other fragments that exhibit similar properties. The matching fragments to the query compound are then reassembled into whole molecules, which may differ from the original but, when considering the individual fragments, fulfill the required functionalities.
Fuzzy pharmacophore searches can be performed on molecule libraries, or even more interestingly, on ultra-large Chemical Spaces. Searching in Chemical Spaces is significantly more efficient, as even trillion-sized spaces can be scanned within seconds for the most relevant molecules that are also commercially available.

BioSolveIT software for fuzzy pharmacophore searches:
  • infiniSee's Scaffold Hopper Mode:
    Mine for similar compounds based on fuzzy pharmacophore matching in the graphical user interface of the Chemical Space navigation platform.
    infiniSee retrieves relevant chemistry from ultra-large Chemical Spaces containing billions or even trillions of compounds based on their similarity to a query compound. Results are synthetically accessible per design in one or two steps and, in the case of our partners' Chemical Spaces, can be ordered directly to your table.
  • infiniSee xREAL: Exclusive platform to screen Enamine's largest compound catalog featuring trillions of compounds.
    infiniSee xREAL also features the Scaffold Hopper.
Command-line tools for fuzzy pharmacophore searches:
  • FTrees: Pharmacophore-based similarity screen. Algorithm behind the Scaffold Hopper Mode.

Augment 2D Methods with 3D

2D methods have the disadvantage that by reducing information to the 2D world, some data points are lost, which can significantly decrease the hit rate. Therefore, it may be beneficial to combine them with other methods to achieve hit enrichment. For example, after performing a fuzzy pharmacophore screening, one could continue working with the results in the 3D world. By using a known binder as a template and subsequently superposing the molecules in 3D, a second virtual screening filter can be applied to enrich promising candidates that resemble active molecules in 3D.

BioSolveIT software for 3D alignment:
  • SeeSAR's Similarity Scanner Mode: Ligand-based virtual screening.
Command-line tools for 3D alignment:
  • FlexS: 3D compound alignment.
Of course, it is a very good idea to extract a large, but still manageable number of molecules from a Chemical Space, and then, if possible, dock them at the target. This method has the advantage of requiring docking of a significantly smaller number of molecules from billions or trillions, which keeps the required computational resources lean.

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