V-SYNTHES from a BioSolveIT Perspective

The V-SYNTHES approach made a significant impact in the scientific community as a new method in structure-based drug discovery. Predicting potentially bioactive molecules among a set of candidates through structure-based methods, commonly referred to as virtual screening, is a widely used practice in the initial phases of drug discovery. This process entails generating molecular poses within a specified binding site of the target, followed by scoring the complexes to establish a ranking. Compounds displaying high-quality interactions with the target are assigned superior scores, serving as an indicator of increased likelihood for experimental activity.

However, this method has its limitations. Processing larger collections of molecules demands extended processing times and significant computational resources. With the continuous growth of commercially available and make-on-demand compound collections, conventional virtual screening approaches may lead to excessively long run times. For instance, dealing with one million molecules could take up to a week, and evaluating a billion-sized Chemical Space might extend into hundreds of years under typical circumstances.

An effective solution to circumvent this issue is the combinatorial exploration of the Chemical Space via Chemical Space Docking.

Why Chemical Space Docking

Efficient Exploration of Ultra-Vast Chemical Spaces

Chemical Space Docking has the capability to efficiently identify the most interesting candidates from Chemical Spaces containing billions or more entries within a reasonable timeframe.

High Success Rates

Chemical Space Docking was able to achieve up to 40% hit rates and to discover novel IP alongside several scaffolds for each target.

Pick your Chemical Space

It was shown that Chemical Spaces overlap only by a fraction. Access to several Chemical Spaces greatly increases your hunting grounds.
Compounds discovered in our partners' Chemical Spaces are commercially available and can be delivered to you within weeks.

Proprietary BioSolveIT Solutions

Chemical Space Docking utilizes BioSolveIT's algorithms FlexX and HYDE for pose generation and binding affinity prediction. Our methods augment the identification of good binders in each stage of the process.

Brute-Force Docking Wastes Time

It was shown that the docking of a large set of molecules yields unfavorable docking scores in over 90% of cases, indicating that these computations are unproductive.
Chemical Space Docking enriches good-scoring compounds and puts the focus on what is important.

Combinatorial Ulta-Vast Chemical Spaces

To understand the concept of combinatorial structure-based built-up of compounds, we need to address its two components: Building blocks and defined chemistry rules.
Building blocks are relatively simple, chemical compounds that are used as materials for the construction of more complex molecules. These compounds usually feature functionalities that enable them to be coupled with other building blocks. The chemistry rules, also referred to as 'reactions', define how building blocks can be processed and connected to each other. Combining both, building blocks and chemistry rules, results in an individual compound collection that covers all possibilities that can emerge from each segment.

The combinatorial Chemical Spaces exceed billions of entries, featuring only synthesizable and molecules.
BioSolveIT collaborates with compound vendors around the globe to create make-on-demand Chemical Spaces with commercially available compounds.

Synthons: Smallest Elements of Combinatorial Chemical Spaces

The structure-based screening of ultra-vast compound collections exploits the nature of combinatorial Chemical Spaces to efficiently identify the most-promising candidates for further investigation.
In the first step, representatives of the building blocks, the so-called 'synthons', are docked into the binding site. Synthons are simplified chemical building blocks with a connection point that represents its potential growing functionality. After assessment of the scored poses, the top-performing synthons are selected for the next step, where all potential combinations with other building blocks are explored.

This approach ensures that synthons displaying suboptimal interactions within the binding site are not persued allowing the focus to remain structures that have the potential to be good binders.

The concept of applying synthons for combinatorial built-up of synthesizable, drug-like molecules was first described by Katritch et al. in the original V-SYNTHES publication (referenced below).

Original V-SYNTHES Publication

Synthon-based ligand discovery in virtual libraries of over 11 billion compounds.

Sadybekov, A.A.; Sadybekov, A.V.; Liu, Y.; Iliopoulos-Tsoutsouvas, C.; Huang, X.; Pickett, J.; Houser, B.; Patel, N.; Tran, N.K.; Tong, F.; Zvonok, N.; Jain, M.K.; Savych, O.; Radchenko, D.S.; Nikas, S.P.; Petasis, N.A.; Moroz, Y.S.; Roth, B.L.; Makriyannis, A.; Katritch, V.

Nature 2021, 601 (7893), 452-459.

Mining the Most Relevant Chemistry

Chemical Space Docking and V-SYNTHES represent efficient methods for giga-screening of massive compound collections.
Beroza et al. have shown that Chemical Space Docking enhances the identification of well-scoring molecules, while brute-force docking of random molecules results in abysmal scores in 90% of the cases. This highlights that combinatorial screening is a resource-efficient approach for pinpointing the most promising candidates within extensive datasets.
Moreover, it has been demonstrated that there is only a small overlap among various combinatorial Chemical Spaces. Accessing BioSolveIT's partner Chemical Spaces extends the scope of molecular exploration since each compound vendor employs distinct building blocks and in-house chemistry. This directly results in a greater variety of molecular motifs, scaffolds, and broader coverage of physicochemical properties.

Last but not least, it is of greatest significance that compounds retrieved with Chemical Space Docking are synthetically accessible. Compounds from our partners' Chemical Space can be ordered and delivered to your table within few weeks.

Chemical Space Docking

BioSolveIT's Chemical Space Docking efficiently retrieves the most promising candidates from one of our partners' Chemical Spaces.
As part of our services, we offer Chemical Space Docking campaigns as a contract research to crack the toughest nuts in small molecule discovery. Our team of experts in medicinal and computational chemistry with decades of experience will help you achieve your goals.

Our approach has already been highlighted in two published success stories.

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Chemical Space Docking Success Stories

Chemical space docking enables large-scale structure-based virtual screening to discover ROCK1 kinase inhibitors.

Beroza, P.; Crawford, J.J.; Ganichkin, O.; Gendelev, L.; Harris, S.F.; Klein, R.; Miu, A.; Steinbacher, S.; Klingler, F.; Lemmen, C.

Nature Communications 2022, 13 (1).

Magnet for the Needle in Haystack: “Crystal Structure First” Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces.

Müller, J.; Klein, R.; Tarkhanova, O.; Gryniukova, A.; Borysko, P.; Merkl, S.; Ruf, M.; Neumann, A.; Gastreich, M.; Moroz, Y.S.; Klebe, G.; Glinca, S.

Journal of Medicinal Chemistry 2022, 65 (23), 15663-15678.