High-Throughput Screening Libraries for Small- Molecule Drug Discovery

Increase the odds of screening success while optimizing efficiency

High-throughput screening involves testing thousands or even tens of thousands of compounds to identify “hits” that bind to the target. The process is like trying many keys to find one (or more) that fit a lock.

The Thermo Scientific Maybridge Screening Collection comprises over 50,000 synthetically derived organic compounds that are structurally and functionally diverse and demonstrate suitable pharmacokinetic properties while excluding potentially problematic structures. These individually designed compounds have been manufactured by Thermo Fisher Scientific using innovative synthetic techniques, based on over 50 years of experience in heterocyclic chemistry. 

The choice of screening library can make or break a small-molecule drug discovery program in its early phases. Our screening libraries are designed to increase the probability of positive results while optimizing cost, time, and effort spent per project. 

Pre-plated high-throughput screening libraries

We offer three pre-plated libraries for high-throughput screening HTS that represent the diversity of the human pharmacophore. The compounds in all three libraries conform to Lipinski Rule of 5 (Ro5) guidelines for “drug-like” properties. They are also designed to reduce false positives by excluding reactive compounds that exhibit covalent bonding, toxicity, insolubility, or oversimplicity.

For libraries focused on specific types of targets, like antibacterial or kinase, see Focused screening libraries below.

Maybridge HTS library comparison table

  Maybridge HitDiscover Maybridge HitFinder Maybridge HitCreator
Product summary

Complete Maybridge Screening Collection

Manageable MSC subset representing its diversity

Extraordinary diversity in a commercially available library

Recommended usage

Complete screen of all our diverse compounds

Easier and more affordable, yet still diverse screening set

Sampling from an even broader and more diverse collection
Number of compounds

>50,000

 14,400 14,000
Source library size 

>50,000 compounds

 >50,000 compounds >500,000 compounds
Excludes reactive molecules




Conforms to Lipinski Ro5

Largely

Available dry film formats
  •  1 µmol in 96-well plates
  • 1 µmol in 96-well plates
  • 0.25 µmol in 384-well plates
  • 1 µmol in 96-well plates
  • 0.25 µmol in 384-well plates
Purity >90%


Diversity filters applied
  • Daylight fingerprinting
  • Tanimoto coefficient = 0.90
  • Daylight fingerprinting
  • Tanimoto coefficient = 0.71
  • Daylight fingerprinting
  • Tanimoto coefficient = 0.65

Focused HTS screening libraries

In close collaboration with an external partner, the Maybridge collection includes target-specified libraries of drug-like compounds created by applying different computational methodologies based upon bioinformatics and structure-based drug discovery. These focused screening libraries of compounds are selected from available collections to facilitate the discovery of novel chemical entities exhibiting specific biological activities or to screen against certain molecular or biological targets. They have demonstrated high hit rates.

Maybridge focused screening libraries

Library Number of compounds Selection criteria
Antiviral >6,000

Small molecules and macrocycles chosen to facilitate the discovery of novel valuable lead compounds with profound antiviral activity and improved safety profiles

Antibacterial

~6,000

Based on proprietary scaffolds (like those occurring in nature) that provide skeletal diversity, combined with the presence of polar functional groups and multiple stereogenic centers
Protein-protein interactions (PPI) >11,000 Selected through analysis of the PPI-relevant chemical space and holistic development of building blocks, fragments, and scaffolds to address disease-relevant PPIs
GPCR >8,000 Selected for screening against G-protein-coupled receptors, including hard-to-target lipid GPCRs
Kinase

>6,000

Chosen to facilitate the discovery of novel kinase inhibitors by providing access to our advanced collection of small molecules, fragments, and macrocycles; compound efficacy validated through in silico modeling and in vitro on-target phenotypic profiling
Protease

>6,000

  
Ion channel

>8,000

 Based on pharmacophore analysis of known ion channel blockers including voltage-gated potassium, sodium channels, and T-type calcium channels
Epigenetics >5,000 Epigenetic compounds including bromodomain-containing proteins and histone methyltransferases

Other focused libraries (such as libraries of compounds that screen against inhibitors of histone deacetylase or HDAC) are available upon request.

Properties and profile of the Maybridge Screening Collection

The Maybridge Screening Collection is widely recognized for its market-leading diversity and quality. In compound screening, the size of your library is not as important as its diversity—inclusion of representative compounds across the “drug-like” space. A highly diverse library of compounds with the right chemical properties is more likely to discover “hits” than larger, less diverse libraries with less suitable chemical properties.

The Maybridge collection comprises structures with complex and diverse properties. In medicinal chemistry, Lipinski’s Rule of 5 (Ro5) is widely considered to be a preliminary measure of a compound’s likelihood to be orally active in humans.1 The Ro5 proposes the parameters (all multiples of 5) listed below as crucial for consideration during drug discovery. Here, we provide the calculated distribution of our Maybridge Screening Collection for each parameter.

Maybridge Screening Collection profile on Lipinski’s Rule of 5 for drug-like properties

Ro5 criterion Maybridge Screening Collection metric
≤5 H-bond donors

99.7% ≤5

≤10 H-bond acceptors

 99.8% ≤10
cLogP ≤5 Mean cLogP = 3.23; 94% in range –0.11 to 6.3
Mol. Wt. <500 Mean mol. wt. = 325; 95% in range 150 to 500

Molecular weight

The ideal molecular weight of a drug compound is less than 500 Daltons. The Maybridge screening collection is composed primarily of compounds that fall within this ideal range.

H-bond acceptors

Compounds containing a maximum of 10 H-bond acceptors are more likely to be orally active in humans. Every structure in our screening collection has M H-bond acceptors or fewer.

H-bond donors

Compounds containing a maximum of 5 H-bond donors are more likely to be orally active in humans. Each structure in our screening collection has 5 H-bond donors or fewer.

Partition coefficient (cLogP)

The calculated partition coefficient (cLogP) provides an insight to the solubility of a compound. This is a critical consideration as drugs must navigate both hydrophobic and hydrophilic environments to reach their targets. Compounds should have cLogP values less than 5, and our Maybridge screening collection is composed primarily of structures that fall within the ideal range.

Rotatable bonds

Compounds containing a maximum of 10 rotatable bonds are more likely to be orally active in humans. Over 90% of our screening collection contain 10 or fewer rotatable bonds.

Partition coefficient (cLogP)

All calculations were performed at Maybridge using the Tsar GD version G.G from Accelrys (salt data was ignored). Definitions from the Tsar Reference Guide are provided below. 

  • H-bond acceptors are defined as accepting a lone pair of electrons to form a hydrogen bond: –O–, C=O, –CN, –N=, 3° amines (excluding sp2), SH, or C=S.
  • H-bond donors are defined as O-H, N-H, and S-H bonds where atoms donate a lone pair of electrons to form a hydrogen bond.
  • cLogP is defined as the sum of the atomic partial log P values. (6)
  • Rotatable bonds are defined as any single order, non-terminal, non-ring, and non-amide bond.

Properties of Maybridge Screening Collection compounds

Property Maybridge Screening Collection attributes
Diversity An independent 1997 study comparing the diversity of 10 commercially available libraries and the Available Chemicals Directory (ACD) showed that out of the libraries that were produced in-house, Maybridge had the most diverse library—the most singletons (clusters with one member) and the highest number of clusters.3
Breadth

When mapped against the World Drug Index (WDI), the Maybridge Screening Collection expresses ~87% of the 400,000 theoretical drug pharmacophores, indicating broad coverage of active moiety space, enabling high impact in screening programs. (Calculations were carried out by Oxford Molecular using Chem-X definition: triplets of H-bond acceptors, H-bond donors, aromatic ring centers, and positive nitrogen atoms.)

ADME profiles

The compounds in the Maybridge collection generally demonstrate good ADME (absorption, distribution, metabolism, and excretion) profiles, which make them strong candidates for development beyond the initial screening assay.
 

HIA (human intestinal absorption) good/poor cutoff set at 40%.4
BBB (Blood-Brain Barrier) BBB+ ≥–0.2, BBB– ≤–0.5, BBB+/– borderline.5,6
Quality

The Maybridge collection compounds are of high quality, based on the analysis of screening compounds by appropriate methodologies including nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (FT-IR), liquid chromatography–mass spectrometry (LC-MS), high performance liquid chromatography (HPLC), and elemental analysis.
 

The purity of the screening collection, unless stated, is greater than 90%, with most compounds having a purity of 95%.
 

Reactive molecules that exhibit covalent bonding, toxicity, insolubility, or oversimplicity are excluded to reduce the number of false positives.
Availability in quantity Typically, about 95% of the compounds in our collection are available in >5 mg stock quantities, over 90% in >50 mg stock quantities, and a large proportion in gram quantities. This means we can ensure a very high level of re-supply of originally tested compounds. We provide most major brands of plates and vials but are happy to use those supplied by customers on request.

Availability in quantity
 

Typically, about 95% of the compounds in our collection are available in >5 mg stock quantities, over 90% in >50 mg stock quantities, and a large proportion in gram quantities. This means we can ensure a very high level of re-supply of originally tested compounds. We provide most major brands of plates and vials but are happy to use those supplied by customers on request.
 

1Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001; 46: 3–26. PubMed

2Viswanadhan VN, Ghose AK, Revankar GR, Robins RK. Atomic physiochemical parameters for three dimensional structure directed quantitative structure-activity relationships. 4. Additional parameters for hydrophobic and dispersive interactions and their application for an automated superposition of certain naturally occurring nucleoside antibiotics. J Chem Inf Comput. Sci. 1989; 29: 163–172. Abstract

3McGregor MJ, Pallai PV. Clustering of large databases of compounds: Using the MDL “keys” as structural descriptors. J Chem Inf Comput. Sci. 1997; 37: 443–448. Abstract

4Zhao YH, Le J, Abraham MH, et al. Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure-activity relationship (QSAR) with the Abraham descriptors. J Pharm Sci. 2001; 90: 749–784. PubMed

5Platts HA, Abraham MH, Zhao YH, Hersey A, Ijaz L, Butina D. Correlation and prediction of a large blood-brain distribution data set—an LFER study. Eur J Med Chem. 2001; 36: 719–730. PubMed

6Crivori P, Cruciani G, Carrupt PA, Testa B. Predicting blood-brain barrier permeation from three-dimensional molecular structure. J Med Chem. 2000; 43: 2204–2216. PubMed

Success stories for Maybridge HTS libraries

The Maybridge Screening Collection has been the source of many successful fragment screening projects.

Olaparib and its Maybridge collection precursor molecule. Olaparib (right, trade name Lynparza), FDA-approved in 2014 for treatment of for BRCA-mutant ovarian cancer, was developed from a compound from our Maybridge Screening Collection (left), one of several such drugs that have received regulatory approval. Olaparib is an inhibitor of poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which includes many ovarian, breast, and prostate cancers. Lynparza is now also a “first-line” maintenance treatment for BRCA-mutated metastatic pancreatic cancer, reducing the risk of disease progression or death in some patients.

Selected hits obtained from the Maybridge Screening Collection that have led to further drug development

For Research Use Only. Not for use in diagnostic procedures.