Structural parameters

We have identified several motifs/fragments/moieties which are abundant in agrochemicals. We used each of the following criteria for compound selection:

• contains 4 or more atoms of halogen (mostly Cl and F);
• has S-containing aliphatic/aromatic ring;
• contains polar, heteroatom-rich functional groups (e.g. diacyl hydrazines, N-acyl urea etc);
• contains oxazole/oxazoline rings;
• contains cyclopropanes;
• has O-containing aliphatic rings.

Structural exclusions

• No alcohols, primary amines and secondary amines occur less frequently in agrochemicals;
• No reactive/toxicophore groups (internal medchem filters). At the same time some compounds bearing active halogen (e.g. 2-chloropyridne) were left in the library;
• “Trivial” scaffolds and chemotypes.

Structural inclusions

• Acidic groups (e.g. carboxylic acids, acylsulfonamides etc.);
• Fsp³-rich molecules;
• Unusual/unique chemotypes/scaffolds/combination of cycles.

Diversity

The internal diversity filter was used to select the most diverse compounds (Coefficient of diversity: 0.86409).

In spite of significant success in medicine in last decades, development of effective new antiviral agents and vaccines continue to be a challenging task for the modern drug discovery. Viruses share most of the metabolic processes of host cells, thereby making difficult search of selective antiviral agents. However, some enzymes are only present in viruses and these are potential and most attractive targets for antiviral drugs.

For instance, there are several key enzymes, which are involved in the processes with nucleic acids like DNA- and RNA-polymerases. Also, reverse transcriptases possess high potential as antiviral targets. The success of previously approved anti-HCV drug Sofosbuvir has demonstrated the potency of small molecules and the important role of viral RNA-polymerases as drug targets. The series of new drug candidates with nucleoside-like scaffolds introduced by Gilead have shown promising results in treating of serious viral infections such as recently emerged Coronavirus, Ebola and RSV.

Examples of nucleoside mimetics as antiviral agents

Remdesivir
Ebola, Junin and MERS viruses
studied against Coronaviruses, 2019-nCoV

Sofosbuvir
Hepatitis C

Entacavir
Hepatitis B virus

Galidesivir
Ebola & Marburg viruses

Ribavirin
RSV infection, hemorrhagic fevers

To meet growing needs in new antivirals Enamine has designed the library of nucleoside-like small molecules, enriched with recently synthesized series of nucleoside-like compounds. The library of carefully selected 3 200 compounds has been pre-plated for most convenient access and prompt delivery in various customized formats.

Library design

Analyzing the structures of known inhibitors we found that most of them are AVR-3200 side mimetics which are not distinguished from the nucleosides by virus enzymes in the active site.

Therefore taking into account pharmacophores and topology of nucleosides and reported nucleoside-like antiviral agents we carefully selected the set of Nucleoside mimetics from our screening collection. The compounds from the set contain natural-like moieties and diverse heterocycles as bioisosters of nucleosides. Additionally, special emphasis has been made on compounds that possess several H-bond donors and potentially can form similar interactions with the protein nucleoside-binding sites as a native nucleoside.

Examples of representative compounds from Antiviral Library

Z1139808866

Z1672058574

Z56769152

Z86230296

Protein kinase inhibitors (PKI) represent an important and still emerging class of targeted therapeutic agents. It is difficult to overestimate the role of protein kinase inhibitors in modern anticancer and immune-oncology therapy. Almost 70 kinase inhibitors have received KNS-64960-4-Z-10 approval, with majority being approved for the treatment of different cancers, and about 200 kinase-targeted drugs are in clinical phase trials.

In order, to bring New Chemistry into this well-explored drug discovery field we carefully designed our Kinase targeted Library. The library is available in pre-plated format and can be promptly delivered in any custom formats. You can receive multiple benefits in the hit follow-up stages and lead optimization by using our Kinase Library:

• Hit confirmation support and hit expansion from dry stock of over 4.4M compounds.
• Straightforward and low-cost analogs synthesis through REAL Database technology.
• Hit-to-lead project support provided in timely manner with broad capabilities available on-site.

You have also an option to screen the librray directly at Enamine. We will be happy to offer you discount on the library cost depending on the collaboration scope.

Library design

In spite of extensive studies and impressive achievements in kinase inhibitor development there is a strong interest in development of novel and selective kinase inhibitors (including allosteric, covalent, bivalent) and subsequently qualitative kinases targeted libraries.

Our previous investigation and detailed structure analysis of known and most potent kinases’ inhibitors yielded the complex approach to design of unique kinase focused libraries. We used several approaches with proven record in development of known successful kinase inhibitors. Validated in silico screening along with selection of compounds bearing privileged scaffolds/moieties and bioisosteric core replacements were the key components of the dedicated design. We also introduced carefully selected compounds that were similar to known drugs.

Hinge Binders sublibrary - 24 000 compounds

Well validated Cores with New Chemistry decoration

Z1757787998

Z3078203034

Z4521999208

Pharmacophore & Shape similarity searches to the set of potent allosteric inhibitors

PD98059 (Allosteric inhibitor of MAPKK)

RS2 (allsoteric PDK1 inhibitor)

MK2206 (allosteric Akt-inhibitor)

Having a pivotal role in multiple cellular processes, protein-protein interactions (PPIs) are responsible for the effects linked to the blockage of the substrate binding site. There are numerous examples of drug candidates that were withdrawn from clinical trials due to the unexpected effects of direct antagonists. This fact outlines the importance of developing new potent protein-protein interactions inhibitors.

We have carefully selected 40 640 diverse compounds specifically targeting PPIs. All compounds are stored as dry substances and they can be acquired in diverse custom formats. Using our PPI Library for hit discovery you receive multiple benefits allowing you to save on time and costs in lead generation:

• Dry stock of over 4.4M compounds for hit resupply and hit expansion.
• Low-cost synthesis of analogues within only 3 weeks through our REAL Database technology
• Medicinal chemistry support enhanced with on-site broad ADME/T panel

You have also an option to screen the Library directly at Enamine. In this case, we will be happy to offer discount on library cost depending on the collaboration scope.

Library design

Systemic analysis of available structural data of numerous PPIs allowed us to develop dedicated approach to the library design. We have analyzed more than 20 different protein-protein complexes to highlight specific features of majority of potent inhibitors in this area. Several specific recognition patterns, like α-helix, β-sheet, PDZ-, PBD and bromodomains were used in the library design. As a result of Ligand- and Structure based in silico screening, we created the selection of compounds featuring:

• Specific recognition patterns, including hot spots analysis, key amino acids, secondary/tertiary structures, α-helices, ‘hot loops’ and specific protein domains affinity.
• Lead-like properties and sp³-rich core structural motifs. Compounds passed all including affiliated MedChem filters including PAINS.
• Latest chemistry and novel building blocks. Identified hits can be readily followed with synthesis of new analogs through REAL Database technology.

Examples of scaffolds populating PPI Library

Importantly, our team of experienced computational, synthetic, medicinal chemists and biologists is ready to address your specific needs in tackling protein-protein interaction of your interest. Please, challenge us with your biological concepts, computational ideas and synthetic designs.