Libraries

FDA Approved and Known Bioactives

The core manages a library of ~4000 small molecules enriched for FDA approved drugs (~1500), and compounds with known pharmacologically activity (~2500).  The library is composed of known kinase inhibitors, cancer chemotherapeutics, inhibitors of epigenetic regulators, GPCR and Ion Channel inhibitors, anti-microbial and anti-viral, with the remaining compounds falling into diverse target classes (e.g. protease, endocrine, metabolism, etc.)

Natural Products

The Core has a library of ~800 purified Natural Products (Microsource) with annotated biological activity.

Diversity Collections

With the assistance of medicinal and computational chemists, the core has assembled a library of 44,000 compounds that were vetted from a set of >500,000 compounds for early stage lead-like characteristics (i.e. modified Lipinski rules, including MW<625 Da, LogP/LogD, Hydrogen  bond donor/acceptors, chiral centers and PSA, functional groups, etc.) required for high-throughput screening.  Additional substructure filters were applied to remove reactive groups (e.g. Michael acceptors) and compounds predicted to be PAINS. Lead Finder Clustering and MACCS fingerprinting was used to select a set of compounds to perform property-based selection of 50,000 compound set of which 44,000 were readily available from commercial vendors. The final library is comprised of 12,000 compounds from ChemDiv’s SMART library, 20,000 compounds from Chembridge’s Core set, and 12,000 compounds from Chembridge’s Express Pick set.  The compound composition of the library can be characterized by an average MW of 350 Da, LogP/LogD of 2.5, Hydrogen Bond donors of 1, hydrogen bond acceptors of 4, chiral centers <1, and a PSA of 60, with ~25% of the library enriched with compounds with known pharmacophore content.

Enamine Antivirals and Nucleoside Mimetics

This is a library of 3933 compounds that consider pharmacophores and topology of nucleosides and reported nucleoside-like antiviral agents.  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.  Selected compounds have attractive drug/lead-like physical chemical and structural properties that are characteristic for nucleosides and their mimetics.

Nucleoside Analogs

Nucleoside analogues represent one of the two drug classes successfully used as antiviral agents. This library of 1111 non-phosphorylated nucleosides (559 purines, 542 pyrimidines, and 6 other) represents the diversity of nucleoside classes. 

Cysteine Protease Inhibitors

A library of 3200 drug-like screening compounds with potential inhibitory activity against cysteine proteases selected with 2D fingerprint similarity to previously defined cysteine protease inhibitors.

Metabolites

We culled the Human Metabolome Database for human fecal and/or microbiota derived metabolites that overlap with mass spec derived metabolomic data.  We have procured, suspended, and formatted ~800 non-redundant metabolites from commercial vendors for high-throughput screening.

Microbial Agonists

A comprehensive collection of 75 pathogen-associated molecular patterns (PAMPs) and other microbial-derived ligands. These ligands are recognized by pattern recognition receptors (PRRs) and can be used as an extensive set of tools to study innate immune signaling pathways in vitro. Five families of PRRs are represented in the library, including ligands for Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs) and cytosolic dsDNA sensors (CDSs).

Fragments

The core has purchase 1500 Bromine containing fragments from the larger Maybridge Ro3 fragment library collection as an aid to X-ray based fragment screening

Quantitative Cancer Target Discovery Platform

We have created a library of 400 cancer related drugs, including 208 FDA approved drugs for cancer indications.  The library is formatted in 2 distinct sets.  The Cancer/kinase set includes 200 drugs against 52 target classes, e.g. topoisomerase, nucleoside analogs, mTOR, EGFR, MEK etc., including 195 FDA approved drugs (54 kinase inhibitors) for cancer indications. The epigenetic set contains 200 drugs and drug-like molecules against 13 molecular target classes, e.g. HDAC, histone methyltransferase, DNA methyltransferase, bromodomain, etc., and includes 20 FDA approved drugs.  Drugs are formatted in 8 pt dose response covering 7 logs of concentration (10 to 0.0001 uM).

Custom Libraries

The HTSC can create custom libraries of small molecules to support specific projects. This allows the investigator to focus on drugs against targets of interest. These can be created at a single concentration or in dose-responses depending on needs.

Silencer® Select Human Genome siRNA Library V4

siRNAs in this library correspond to each of 21584 genes, with 3 unique, non-overlapping siRNAs provided per target for a total of 64752 siRNAs. The so called target genes correspond to >98% of genes listed by NCBI that have at least one or more curated RefSeq coding transcripts. The siRNAs were designed to hit all RefSeq coding transcripts of that gene that were known at the time of design.   The library contains:

1. Human Druggable Genome: 27,093 unique siRNAs targeting transcripts from each of 9,031 human genes.
2. Human Druggable Genome Extension Set: 4,149 unique siRNAs targeting transcripts from each of 1,383 human genes.
3. Human Genome Extension Set: 33,510 unique siRNAs targeting transcripts from each of 11,170 human genes.

The siRNAs targeting the ―druggable portion of this library are arranged by gene functional class (i.e. kinome, GPCR, etc.) to enable easy screening of important gene subsets in small scale screens.

Silencer® Select Human Lnc siRNA Library

The siRNAs in this library correspond to each of 2220 long  non-coding RNAs, with 3 unique, non-overlapping siRNAs provided per target for a total of 6660 siRNAs.

mirVanaTM Human miRNA Mimic Library V20

This library contains 2555 unique human microRNAs mimics.  MicroRNA mimics are double stranded oligonucleotides that effectively mimic mature endogenous miRNA function to elucidate biological pathways, identify and validate miRNA targets, and identify miRNAs that regulate gene expression.  The design of this library is based on miRBase v.20.

mirVanaTM Human miRNA Inhibitor Library V20

This library contains 2555 unique human microRNAs inhibitory hairpins.  MicroRNA inhibitors are chemically modidies single-stranded RNA inibitors of endogenous miRNAs. The design of this library is based on miRBase v.20.

Mammalian Gene Collection (MGC) cDNA Library

This library contains 18,000 full length, fully sequenced confirmed cDNAs from human and mouse pre-cloned into the pSPORT6 expression vector.  cDNA expression is driven by a CMV promoter. We have the bacterial glycerol stocks of the library and arrayed purified plasmid DNA ready for screening.  Investigators can also purchase individual clones.

Human TRC shRNA Library

This library (TRC-Hs1.0) targets 15,000 annotated human genes and consists of 80,700 precloned constructs.  The hairpin sequences, a 21-base stem and a 6-base loop, are each cloned into the pLKO.1 vector, which allows production of replication-incompetent lentiviral particles, transient or stable expression of the shRNA, and antibiotic (puromycin) selection of transfected or infected cells.  On average, each gene is targeted by ~5 constructs.  The shRNA sequences for a given target are distributed throughout the cDNA sequence of a target, including a shRNA clone targeting the 3’UTR for use in phenotypic rescue studies using cDNA expression constructs.  For more information about the library, including shRNA target selection and genes targeted, visit http://www.broad.mit.edu/rnai/trc/lib. Investigators can purchase individual clones.

MGC premier Lentiviral ORF Expression Library

A human ORFeome library of 13,000 arrayed ORFs that represent approximately 11,373 genes, precloned into pLX304, which allows production of replication-incompetent lentiviral particles and antibiotic (blasticidin) selection of infected cells. For added convenience the lentiviral ORF expression vector was created to enable expression of a protein of interest with a V5 fusion tag for western blot detection, puri¬fication, co-immunoprecipitation, protein localization and FACS analysis.

Custom Libraries

The HTSC can create custom libraries of genetic reagents (cDNAs, siRNAs, shRNAs) to support specific projects. This allows the investigator to focus on gene sets of interest.