Chemical Compound Collection

Filtering

Compounds were filtered to eliminate toxic and reactive functional groups (REOS score ≥ -2,)^[1] and the following physical property criteria: 200 <= MW <= 600; AlogP <= 6; #H_acc <= 10; #H_don <= 5. We intentionally allowed slight deviations from the ‘rule of five’^[2] in order to permit slightly larger and more lipophilic compounds to be included since we anticipate screening some protein-protein interaction targets where these characteristics may be required for hit identification.   Because this compound set was focused on maximizing Murcko scaffold diversity, all compounds were required to have at least one ring, as only such compounds have Murcko scaffolds.

[1] Walters, W.P. and Murko, M.A. “Prediction of ‘drug-likeness’” Advanced Drug Delivery Reviews 54 (2002) 255-271.

[2] Lipinski, C.A. “Lead- and Drug-like compounds: the rule-of-five revolution” Drug Discovery Today 1 (2004) 337-341.

[3] Bemis, G.W. and Murko, M.A. “The Properties of Known Drugs. 1. Molecular Frameworks” J. Med. Chem. (1996) 39 2887-2893.

Murcko Scaffold Generation

Compounds were selected based on structural diversity at the Murcko scaffold level. Essentially, a compound’s Murcko scaffold includes contiguous ring systems plus chains that link two or more rings. For Murcko scaffolds which contained more than 20 compounds, twenty compounds were randomly selected for that scaffold in order to maximize the diversity of scaffolds available for diversity set creation by effectively limiting the population of single scaffold-based compound sets.

Compound Acquisition

Based upon the above selection process and previous experience with vendors known to be reliable for delivery and purity, a set of 100K compounds was chosen and purchased from Enamine. In addition to determination of identity and purity at the time of hit identification, 3-5% of this collection will be examined by LC/MS for identity and purity confirmation – ongoing.

Pre-plated 50K DIVERSet-CL Library compounds; Pre-plated 7K CORE Library Stock compounds.

50K diversity compound set from Life Chemicals with little significant overlap with the other CICBDD diversity collections.

Compounds were selected from >100K compounds reviewed from Life Chemicals, ChemDiv, Asinex and Enamine kinase-focused libraries.  Compounds were selected based on similarity to known kinase inhibitors as well as compounds having a hinge-binding motif (e.g. heterocycles with a high likelihood to bind the kinase hinge motif conserved in nearly every kinase-small molecule X-ray structure) and structure/ligand-based virtual screening.  UNC CICBDD acquired 5K compounds that were unique when compared to the UNC 100K diversity set.   10K kinase-directed compounds were identified in the diversity set and included in the kinase set to yield 15K total kinase-directed drug-like small molecules.   All compounds are stored in barcoded 384 well microplates to ensure proper compound identification.  All of these compounds were rule of 5 compliant.ⁱⁱ

A panel of small-molecule epigenetic modifiers (approximately 1,000 compounds), which includes inhibitors of histone methyltransferases (HMTs), methyl-lysine reader proteins, histone demethylases (HDMs), DNA methyltransferases (DNMTs), histone deacetylases (HDACs), and acetyl-lysine reader proteins.  We will continue to add compounds synthesized for our ongoing HMT and methyl-lysine reader protein inhibitor discovery programs to this panel.

The GPCR Targeted Set contains 860 compounds selected from known GPCR effectors and from internal synthesis from internal synthesis programs including functionally selective D2 ligand chemistry.

The LOPAC set is a library of 1280 known bioactive small molecules (includes 300 FDA approved drugs) including Antibiotics, Gene Regulation & Expression, Multi-Drug Resistance, Apoptosis, Ion Channels, Neurotransmission, Calcium Signaling, Lipid Signaling, Phosphorylation

The LCGC Library contains108,000 diverse compounds provided from a collaboration with Lankenau Institute for Medical Research (LIMR) Chemical Genomics Center (LCGC).  These compounds are provided as orthogonal pools of 10 compounds/well.

The Southern Research Library contains 13,392 compounds from a collaboration with the Southern Research Institute.  These compounds are the product of >20 years of internal drug discovery synthesis and have only been made available to a limited number of collaborators outside Southern Research.

This is a single 384 well plate that contains 32 compounds that are known kinase inhibitors arrayed in 10 point dose curves. It includes Chelerythrine Chloride, Genistein , Wortmannin, Tozasertib,  H-89, U0126, Lapatinib Di-p-toluenesulfonate, SB 203580, SP600125, SB202190, Dovitinib, Tyrophostin AG490, Gefitinib, Lestaurtinib, Dasatinib, Sunitinib, Malate Salt, Imatinib, Masitinib, Sorafenib, Tofacitinib, Saracatinib, K252a, PD 184352, Staurosporine, Erlotinib, Enzastaurin, Axitnib, Canertinib, GDC-094, LY294002 and Quercetin.

A CICBDD-designed set of well characterized kinase inhibitors, either clinical compounds or compounds in clinical trials.

GlaxoSmithKline (GSK) released a sets of 367 (set 1) and 539 (set 2) ATP-competitive kinase inhibitors from published accounts of proprietary drug discovery efforts (PKIS: published kinase inhibitor set).

The Kinase Activator Library is a small library of potential allosteric kinase activators selected from a database of commercially available compounds using pharmacophore-based virtual screening. The pharmacophore model was built based on the co-crystallized allosteric PDK1 ligand.

A set of clinically-relevant compounds from the NCI.

A unique collection of nucleotide/nucleoside and nucleotide/nucleoside analogue compounds.

This library is built from Enamine building blocks with a variety of warheads: only experimentally confirmed reactivity, no over-reactive warheads, no alternative reactive functionalities.

This library from MedChemExpress is a unique collection of 1503 compounds that may have anti-COVID-19 activity for high throughput screening (HTS); compounds are derived from virtual screening of approved compound and clinical compound libraries based on the 3CL protease, Spike Glycoprotein and ACE2 structure.

Over 9,000 compounds have been synthesized for a wide variety of hit-to-lead and lead-to-candidate campaigns since the start of the Center in 2007. All compounds are high quality with LC/MS traces and NMR spectra completed to confirm purity and structure and these data are associated with the compounds at registration in the LIMS. These compounds are currently being assembled and registered in 384-well plates for screening campaigns.

This DNA-encoded chemical library was designed and synthesized in the CICBDD using combinatorial fragment assembly coupled with a DNA barcoding strategy where each three-part small molecule is identified via a unique DNA barcode.