SAR by Space: Enriching Hit Sets from the Chemical Space

Abstract

We introduce SAR by Space, a concept to drastically accelerate structure-activity relationship (SAR) elucidation by synthesizing neighboring compounds that originate from vast chemical spaces. The space navigation is accomplished within minutes on affordable standard computer hardware using a tree-based molecule descriptor and dynamic programming. Maximizing the synthetic accessibility of the results from the computer is achieved by applying a careful selection of building blocks in combination with suitably chosen reactions; a decade of in-house quality control shows that this is a crucial part in the process. The REAL Space is the largest chemical space of commercially available compounds, counting 11 billion molecules as of today. It was used to mine actives against bromodomain 4 (BRD4). Before synthesis, compounds were docked into the binding site using a scoring function, which incorporates intrinsic desolvation terms, thus avoiding time-consuming simulations. Five micromolar hits have been identified and verified within less than six weeks, including the measurement of IC50 values. We conclude that this procedure is a substantial time-saver, accelerating both ligand and structure-based approaches in hit generation and lead optimization stages.

Generating Multibillion Chemical Space of Readily Accessible Screening Compounds

“…Further extension of this concept led to the development of the REAL Space, a searchable chemical space that is not typically stored as an enumerated database but generated upon query through a chemoinformatics software ( Klingler et al., 2019 ). This feature tree-based ( Rarey and Stahl, 2001 ; Boehm et al., 2008 ) engine allowed processing very large datasets currently reaching 13 billion molecules.…”

Novel prediction methods for virtual drug screening

“…For example, disk size required to save 10 20 molecules as SMILES is 200 000 TB in compressed format [34]. Techniques aimed at optimizing data-handling in large libraries are beyond the scope of this article and an interested reader can find more information about it from Merck's Accessible Inventory (MASSIV) [35] which is currently one of the largest virtual molecule pools known to the public.…”

Unprecedented Potential for Neural Drug Discovery Based on Self-Organizing hiPSC Platforms

“…One example was describe by Klingler et al, where they introduced a concept for accelerated discovery of structure-activity relationship (SAR) for enrichment within the large chemical space. The space navigation is accomplished within minutes on affordable standard computer hardware using a tree-based molecule descriptor and dynamic programming [57]. The approach is significantly timesaving, taking advantage of the "chemical space", accelerating hit generation and huge optimization in drug design.…”