The main emphasis in the library design was made on drug-like compounds enriched with H-bond donors (possess at least two H-bond donors) and bearing nature-like Fsp³–rich scaffolds with diverse spatial orientation of H-bond donors and different 3D-shapes. We suppose the library application would identify new attractive chemotypes which correspond to drug-/lead-like criteria and on the other hand participate in key interactions similar to glycoside binding in the active site of the targets.

Library design

• Privileged core fragments and side chain functionalities:
  • cyclic amino alcohols, cyclic glycols
  • O,N-containing aliphatic rings
  • polyalcohols
• Nature-likeness scoring algorithm: Taverna 2.5 workbench, similarity to available NP databases
• MedChem structural filters, removal of common and trivial chemotypes: PAINS, REOS, Elli Lily rules and strict Enamine filters

Training set of known glycosides was collected from the public available e-databases, scientific literature and evaluated to define the optimal range of molecular parameters.

Examples of the molecules in the library

Z1566350909

Z57176224

Z111676358

Z1815149232

Z1803448333

Z1618873981

Z1544404493

Z2053729005

Mimetics of nucleosides are special class of proven therapeutic agents, which already showed high efficacy in treatment of viral infections, cancer and bacterial disease. In spite of similar structural motifs and common moieties and even cores, many modified nucleosides display high selectivity to certain class of targets. This type of molecules is well-tunable when using at least two sites of possible modification. Recently, we developed few alternative parallel chemistry approaches to make these compounds more accessible within reasonable time and in cost-effective manner. Using our library for your hit finding you receive multiple benefits:

• Hit Confirmation support – resupply from dry samples, QC check, HPLC repurifiction, guaranteed resynthesis.
• Straightforward synthesis of follow-up libraries through our REAL Database technology.
• Medicinal chemistry support enhanced with on-site broad ADME panel.

Library design

• Careful Substructure Search
  Search of nucleoside core fragments and their bioisosteric heterocycles with simultaneous presence of sugar-like moiety
• Strict MedChem Filters
  Removal of undesired functionalities, reactive groups and large aromatic fragments
• Chemotype Control
  Compounds with trivial structural fragments were mostly removed. Control of renovation of the library in accordance to new literature data.

Design of REAL Nucleoside mimetics dataset

REAL structures with validated synthetic procedures

• Combinatorial approach
  Over 100 000 Building Blocks immediately available for modification:
• Diazine heterocyclic cores mimic nucleobases
• alicyclic amino alcohols - sugars
• Filtering of unwanted functionalities & MedChem inspection
• Automated parallel synthesis
  Implementation of well-developed reaction procedures operated by highly experienced staff

Design of REAL Nucleoside mimetics dataset

Recently, it was proposed that fragments with a single pharmacophore (i. e. polar group or other moiety for binding to a protein) have advantages over those with multiple, distally separated functional groups. This design approach is believed to maximize the advantages of FBDD, first of all through increasing synthetic capabilities of the fragment growth at the hit follow-up step. Applying these guidelines, we have created a library of single pharmacophore fragments.

Key features:

• All the compounds pass both strict “ Ro2-like” physicochemical and most stringent in-house structural filters excluding PAINS, highly reactive and toxic motifs.
• High variety of both pharmacophores and scaffolds bearing them
• Rapid follow-up/fragment growth using both readily available in-stock and synthetic analogs from Enamine Fragments, Screening Collection and REAL Database

Examples of the molecules in the library

Z335451498

Z856211078

Z1862025182

Z235363021

Z1270257271

Z90663552

Z1625067638

Z1255452234

The library was designed in cooperation with research group at University of Cambridge, UK, to be a universal tool for initial screen of novel targets. All compounds in the library have been tested for water solubility and chemical stability in buffer solution to afford a small library of 320 fragments compounds. Our Essential Fragments are especially suitable for the purposes limited by different factors, e.g. validation of new targets, excessive cost of setting up a library for one or two targets, assay particularities etc. In these cases thorough selection of high quality of compounds is extremely important for the successful research.

Key features

• Increased hit probability – the structures are based on frequently reported fragment hits and scaffolds derived from experimentally determined structures of protein-ligand complexes.
• Suitable for different screening assays such as fluorescence polarization anisotropy, SPR, ligand-based NMR, thermal shift etc.
• Experimentally assured solubility at 1 mM, 2mM concentrations in PBS buffer and at 200mM in DMSO solution.
• Experimentally confirmed chemical stability in aqueous buffer solution (pH 6.5–7.5) at 30 °C for 24 h (by LC-MS method)
• Compounds with fluorescence interference at 488 or 520 nm and as well as compounds with affinity to CMD-coated surfaces were removed.

Examples of the molecules

Z56899125

Z385412938

Z404012058

Z364003330

Z363993550

Z1251357721

Z364250128

Z199451530