Chemical Building Blocks

Chemical building blocks are the fundamental units in drug discovery. They contain functionalities that allow them to be linked together, leading to the creation of new, larger compounds. In small molecule drug discovery, access to suitable building blocks essentially defines what can be synthesized as a drug candidate.

Recognizing this, numerous companies have specialized in providing building blocks and compound delivery as part of their business model. Research institutions can order the specific building blocks they need or even fully assembled compounds, significantly reducing the effort required for in-house synthesis. By specializing in this area, these companies can offer both at competitive prices, which results in cost savings compared to producing them internally.

Creating Drug-Like Compounds

Building blocks are characterized by having a functionality or functional group that enables their coupling with other building blocks. This functionality can essentially be anything, as long as there is a suitable reaction to link it with another functional group. Common examples include carboxylic acids and their derivatives, amines, aldehydes, alkylating agents, and more. Additionally, other functional groups or entire ring systems can be formed through cyclization reactions that combine two or more building blocks into a new, larger molecule.

The most common reactions in medicinal chemistry can be here and here.

Chemical Building Block Providers

There is a wide range of global building block providers. It’s always worthwhile to check with several sources when searching for a specific building block since each provider offers a unique catalog (which makes sense, as every company needs a unique selling point). Additionally, it’s smart to pay attention to pricing.

In the context of generating Chemical Spaces, we collaborate with several building block and compound suppliers who cater specifically to the needs of drug discovery. Our partners include the following:

Get the Most out of Chemical Building Blocks

Building blocks expand the toolkit available to medicinal chemists. The more building blocks that are accessible, the greater the diversity that can be incorporated into compounds. However, the term “extension” also implies that building blocks only reveal their full potential when combined with an organization's in-house collection of other building blocks and molecules. Often, the true intellectual property (IP) value comes from what is not readily available to everyone.

The final piece to fully leveraging building blocks is the use of chemical reactions to unlock all possible compounds that can be synthesized from them. Combinatorial chemistry is not a new concept; it has been utilized for decades in the pharmaceutical industry to explore new areas of the accessible chemical space.

Chemical Spaces - Results of Powerful Combinatorial Chemistry

The number of possible compounds that can be synthesized grows exponentially with the increase in the number of building blocks and the reactions used to combine them. Pharmaceutical companies have recognized this and have integrated their in-house reactions with proprietary building blocks alongside commercially available ones. The result is the creation of massive compound superclusters containing accessible, drug-like compounds.

What makes these combinatorial Chemical Spaces unique is that, due to their setup, they are not limited by the constraints of enumerated libraries. Even screening through trillion-sized chemical spaces is not an issue and can be achieved in minutes or even seconds.

BioSolveIT software for generation of Chemical Spaces:

CoLibri: The command-line tool CoLibri generates combinatorial Chemical Spaces using input from chemical building blocks and reactions for combining them. Due to the combinatorial explosion, even a manageable number of both can yield quite large numbers. Several assistive features are available to simplify the initiation of space generation.

Platforms for Chemical Space exploration:

infiniSee: Chemical Space navigation platform with a graphical user interface.
infiniSee retrieves relevant chemistry from ultra-large Chemical Spaces containing billions or even trillions of compounds based on their similarity to a query compound.
SeeSAR's Chemical Space Docking™:
After generation of your Chemical Space it is also possible to use it for structure-based 3D approaches to predict active compounds on a target of interest.

Command-line tools for Chemical Space exploration:

FTrees: Pharmacophore-based similarity screen. Algorithm behind the Scaffold Hopper Mode.
SpaceLight: Retrieves close analogs based on molecular fingerprints. Algorithm behind the Analog Hunter Mode.
SpaceMACS: Performs maximum common substructure searches, as well as exact substructure mining. Algorithm behind the Motif Matcher Mode.

Get Creative with Your Building Blocks

If structure-based projects can be implemented within the company and structure-activity relationships are frequently explored, the building blocks (both in-house and commercial) can be efficiently used for compound ideation and lead optimization.

FastGrow; FastGrow is a pocket exploration tool. What sets it apart is its ability to swiftly scan through the conformations of hundreds of thousands of molecular fragments to find the best-fitting solutions that complement the binding pocket.

Users can generate their own fragment databases by attaching building blocks with an extension vector, which specifies where they will attach to the ligand of the complex. This flexibility opens up exciting possibilities to explore how a ligand can be improved through extensions using fragments generated from these building blocks.

FastGrow is available as command-line tool and is part of SeeSAR's Inspirator Mode.

Excited for more drug discovery solutions?

Keep on exploring!

Chemical Building Blocks