YoctoReactor Libraries

Chemical building blocks (BBs) are brought into close proximity which facilitates chemical reaction and the attached DNA ultimately encodes the final product.

The overall design has favorable implications for the scope and reliability of the chemistry, the stability of the structure, and, ultimately, the capability for addressing the most challenging targets. 100% correspondence between code and synthesized compound is ensured by purification steps using the DNA as purification handle after each chemical step.

A fundamental difference between conventional HTS screening and DEL, is that hits identified by DEL screens need to be resynthesized off DNA. Therefore, we have a particular focus on a low false positive rate.

• A library consists of hundreds of millions of DNA-encoded small molecules formed by combinatorial self-assembly of DNA-encoded BBs
• The identity of the product is easily determined by DNA sequencing
• The yR affords precise control of chemical reactivity and deconvolution

The chemical building blocks (BBs) are responsible for the vast majority of atoms and bonds in the library compounds. Consequently, BBs represent our primary focus for generating chemical diversity. We use commercial available BBs when possible, but are using in-house designed BBs in increasing numbers to satisfy the need for generating interesting and novel diversity.

• More constrained structures
• More complex structures
• Less rotatable bonds
• Novel heterocyclic motifs
• More tertiary amides (better solubility, membrane permeability, plasma and metabolic stability)

• Type – Trimeric format
• Size – 522 million (1 compound – 1 unique DNA code)
• Synthesis – Robust and reliable: 2 different chemistries in 2 steps: acylation and reductive amination
• Novel compounds – High: 99.9% with a Tanimoto similarity score < 0.95 with ChEMBL
• Toxicophores – Low: ⁓0.4%
• Oral bioavailability – High: 99.2% in compliance with Ro5 (MW 529 Da and cLogP 0.75 on average)
• Aliphatic content – High: Fsp3 = 0.6 on average (good for solubility and provides 3D structures)
• Diversity – High: Driven by BBs – carefully designed and chosen for pharmacophore motifs, 3D orientation and even grid-size
  • Building Blocks – High:
    • 1327 different BBs
      • 795 designer BBs
      • 572 commercially available BBs
  • Scaffold diversity – High: 341 different 
  • Topological diversity – balanced:
    • Rigidity/flexibility: 0.45 on average (rigid<0.5<flexible)
    • Shape index: 0.59 on average (Spherical<0.5<linear)
    • 3D optimized