targeted diversity

The main goal of this approach is to create a thoughtful and multi-purpose diversity and incorporate it into one single compound library for different screening purposes. Those may be:

1.  “Difficult” targets (no target / ligand structure(-s) known, study and interrogation of cellular processes (e.g. apoptosis, cell cycle, etc.);
2.  Signaling pathways (e.g. WNT, Hh, RTK, Ras, etc.) and “eclectic” biological targets, including cellular processes (e.g. apoptosis and cell cycle);
3.  Protein-protein interaction (e.g. XIAP, pGPCRs, etc.);
4.  An entire selected therapeutic area that incorporates multiple biological targets.
The “Targeted Diversity” approach encompasses the superposition of a highly diverse chemical space on the selection of divergent families or sub-families of targets and unique bio-molecules. This is also a universal approach, for it can be used to design and/or select high quality libraries of drug-like compounds focused on individual therapeutics areas or pathways.

As a starting point, the following main target families (encompassing 300+ various targets in total) are to be considered:

1.  GPCR target family;
2.  Ion channels (both ligand- and voltage-gated);
3.  Nuclear receptors;
4.  Enzymatic targets (kinases, phospho-diesterases, phosphatases, proteases, HDAC, sulpho-transferases, etc.);
5.  Transporters (serotonine transporters, dopamine transporters, amino-acid transporters);
6.  Effector proteins (pro- and anti-apoptotic, BCL2, diablo, entegrines, etc.).

Each of these target families includes various orthogonal targets that are annotated as interacting with small molecules. Such small molecule “prototypes” are used to select small focused sets against each individual target from a given target family. These “single target focused sets” are already refined by Lipinski’s Rule of Five (Ro5) and ChemDiv’s in-house medicinal chemistry filters, and form a “starting” chemical space for follow up refinement and final library selection. Based on the defined “refinement” criteria a certain number of compounds from each “single target focused set” is selected, thus forming the final “Targeted Diversity” Library.

Such “refinement” criteria include, but not limited to:

1.  Available annotation data (literature, patent search, in-house research);
2.  Diversity of scaffolds and their further population with individual compounds;
3.  Bio-isosteric replacement strategies, e.g. known peptide ligand may be substituted with a small non-peptide peptidomimetic;
4.  Computer-assisted 3-D pharmacophore matching;
5.  Special preference is given to chemotypes with functionality mimicking recognition elements (shapes, “warheads”) of known active ligands/inhibitors for considered targets;
6.  Special preference is also given to scaffolds with good IP potential (as evidenced by Reaxis and SciFinder sub-structure searches);
7.  Ro5 (Lipinski’s Rule of Five) and ChemDiv’s in-house medicinal chemistry filters (MCF-1,-2,-3,-4);
8.  Water Solubility;
9.  75 < PSA < 100;
10.  Presence of sp3 carbons.

The current generation of ChemDiv’s Targeted Diversity Library is built around 2,500 diverse chemical scaffolds and includes 50,000 individual drug-like molecules. Embellishment of this library is an ongoing effort at ChemDiv, and regular updates are made as newly designed and produced compounds become available and pass our QC specifications (>90% purity as established by LC/MS with UV and ELSD). Additionally, new proposals for target-specific sets are being evaluated, tested and made available.

Examples of the focused sub-libraries tat form the current generation of ChemDiv’s Targeted Diversity Library include:

•    GPCR
•    Ion Channels
•    Kinases
•    Developmental pathway modulators library
•    Acetyl-CoA library
•    AKT Kinase library
•    alpha2-Adrenoceptor Antagonists
•    AntiApoptotic library
•    ProApoptotic library
•    Serotonine receptors library
•    Arginine Kinase library
•    Aurora A/B Kinase library
•    Bcl-2 / MCL1 library
•    Bradykinin library
•    c-Met Kinase library
•    CB1 / CB2 library
•    Cl- channels library
•    CNS library
•    CXCR 1/2 library
•    EphB4 inhibitors library
•    Frequent Hitters library
•    FSH agonists library
•    GABA (A) library
•    Glutamate (mGluR) library
•    Glucokinase activators library
•    GSK3b library
•    HDAC library
•    HSP90 library
•    IGF-1R library
•    K+ channels library
•    Methyltransferase inhibitors library
•    mGluR ligands
•    MK2 inhibitors library
•    Na+ channels library
•    NAChR library
•    p2x7 focused library
•    PDZ library
•    Phosphatases library
•    PI 3-Kinase library
•    Purinergic library
•    RAR library
•    Secretase library
•    Serine / Cysteine Proteases inhibitors library
•    Steroids / steroid-like library
•    Sulfotransferase inhibitors library
•    Transporter inhibitors library
•    Kinase library

Explore other libraries:

Discovery
Focused Libraries
Fragments and beyond
Peptidomimetic Libraries