Cambridge MedChem Consulting

Fragment Collections

An increasing number of commercial companies are now offering well defined fragments for screening, as might be expected there is significant overlap between the various companies however most also contain unique fragments. Several approaches have been described in the design of fragment libraries and more details are available here. Most comply with the commonly accepted Astex "Rule-of-Three" (MW <300, H-bond donors/acceptors <=3, cLogP <3). Ideally they should also have solubility measure.

Fragment Libraries with details taken from the company websites.

3D Fragment Library Consortium The 3D Fragment Consortium brings together UK-based not-for-profit drug discovery institutes and academic groups, working in partnership to build a collection of chemically diverse molecules with a particular focus on fragments that incorporate 3D structure. The consortium is looking to collaborate with other research groups to expand the collection and make it available for screening against new biological targets to help kick-start hit discovery programmes and provide a foundation for a vibrant pre-competitive drug discovery network across the UK. The 3D Fragment Consortium has identified a foundation library of 170 fragments to commence their screening activities.

AnalytiCon The FRGx library contains fragments taken from Natural Products, all Fragments: clogP < 3.0; MW < 300.0 in >95% purity with good solubility claimed. The samples are available in 10-100 mg amounts with resupply in multigram amounts.

AnCoreX AnCore’s fragment libraries consists of 500-1000 fragments specifically targeting metallo-protein active sites. More than one-third of proteins contain a metal ion. Many attractive drug targets contain a free sulfhydryl group in the active site that confounds functional HTS assays due to its facile, non-specific oxidation leading to target inhibition. We have developed a Targeted Covalent Inhibitor fragment library (TCI-Frag™) containing 100+ Rule-of-3 compliant fragments are conjugated with mildly reactive functionalities.

Asinex BioFragments comprises of 1300 especially small compounds ideal for fragment-based screening. These compounds are in essence bare templates that have been carefully decorated with ‘small caps’ - very low molecular weight peripheral building blocks. Molecular Weight 120-250, cLogP <2.5, HAC 9-18, HBA < 7, HBD <4. Asinex also provide a fragment to lead set designed for fragment growth and elaboration.

Beryllium Discovery. Currently at over 2000 fragments, the FOL compound collection can provide critical starting points for lead compounds based on metabolites found naturally in cells. The FOL contains actual metabolites and natural products that follow “Rule of 3” guidelines, plus fragments and derivatives of metabolites to give broad coverage of the human metabolome in fragment space.  The FOL also contains several hundred biaryl protein structure mimetics with the potential to target "hot spots" of protein-protein interaction sites.  The Fragments of Life™ collection is available for screening by several methodologies, and is designed to leverage structure-guided lead discovery for any target of interest. Key concepts in library design, proof of principle: Davies et al. (2009) “Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography.”  J. Med. Chem. 52: 4694–4715.   Detailed methods on FOL screening by X-ray crystallography: Begley, D.W. et al. (2011) "Fragment Screening of Infectious Disease Targets in a Structural Genomics Environment." Methods Enzymol. 493: p. 533-56. Detailed methods on FOL screening by NMR spectroscopy: Begley, D.W. et al (2011) "Leveraging Structure Determination with Fragment Screening for Infectious Disease Drug Targets." J Struct Funct Genomics. 12(2): p. 63-76.

BioFocus Library of 1500 compounds (no details) Recent library enhancements include BioFocus' 3D-biased fragment sets, FRG04 and FRG05, which are also available to purchase as sets. As part of the design of these libraries proprietary computational tools have been developed to assess the shape profiles of fragment collections, including 3D-biased.

ChemBridge The Fragment Library set, comprising approximately over 7000 compounds, was chosen based upon the commonly accepted Astex "Rule-of-Three" (MW <300, H-bond donors/acceptors <3, cLogP <3) as well as the established proprietary ChemBridge substructure filters. The commonly publicized cLogSw (predicted aqueous solubility) lower limit can be as low as -3.50, however, the -2.50 limit (approx. 3mM) applied by ChemBridge ensures a higher predicted aqueous solubility. The set includes compounds with available, as well as protected, functionality. All compounds in the collection are available in stock and may be cherry-picked or taken as a complete set.

ChemDiv The current library contains nearly 5000 compounds, molecular weight 96 to 301, HBA <6, HBD <5, logD -8.0 to 5.17 and are predicted to have good water solubility. The fragments selected contain only C, H, N, O, S, P, F, Cl, and Br atoms. Fragments with undesirable properties are eliminated by applying our special medicinal chemistry filters. The library contains 615 unique heterocycles.

Domainex A new and unique collection of chemical fragments to provide its clients with a diverse range of starting points for discovery programs. The fragment collection has considerable advantages over other commercially-available collections of fragments, as it contains a more diverse range of pharmacophores without any increase in lipophilicity.

Enamine The Enamine Fragment Library was designed by application of "Rule of three" filters proposed by Astex Therapeutics [DOI: 10.1016/S1359-6446(03)02831-9] and then strict structural filters [DOI: 10.1007/s11030-006-9040-6] to a combined dataset of Enamine Screening Compounds and Building Blocks (940,000 and 19,000 respectively at the time of the library preparation). Criteria used in ADME selection are summarized in Table 1. We had identified 19,765 compounds strictly meeting these requirements. This set of compounds was clustered and subjected to diversity sorting, resulting in selection of 1,500 compounds offered as the Golden Fragment Library. Golden Fragment Library perfectly represents entire pool of fragment-like compounds of Enamine Screening Collection. Remaining 27,000 compounds were organized into the Fragment Library.

i2c i2C have a fragment collection of 1700 molecules, of which 15% are unique molecules generated by in-house synthesis. The fragments generally follow the usual “rule of three” profile. Average Molecular Weight = 187, Average SLogP = 1.8, Average TPSA = 48, Average heavy atom count = 13.

InFarmatik We now offer 300 diverse 3-D fragments from stock and a Synthesis OnDemand fragment library based on validated chemistry which contains over 8400 new and diverse 3-D fragments. In addition we have a set of 293 in-stock Ro3 compliant 2-D fragments.The 3-D fragment compounds are not common experimental substances. They were specifically designed as fragments and not just filtered out from publicly available compound sets, as many of our competitors have done. About half of them are diverse spiro shape compounds. They are new and original, therefore their IP field is still not overloaded, making them easily patentable. Most of the compounds have soft scaffold structures: meaning they were designed to have low reactivity centers to avoid non-specific binding, while preserving the ease of chemically coupling them to each other or to other fragments. All non-specific binding groups (strong acids, bases and reactive moieties) are omitted. The attachment points in the molecules in many cases are useful for region specific reactions. Some of the fragments fit the criteria of being scaffolds as well. Average MW=238, average clogP=1.6, confirmed experimental water solubility in 0.1% in 2% aqueous DMSO with stability data. We also offer custom fragment analog synthesis and fragment coupling services.

IOTA Fragments in IOTA's "Diverse 1500" Library have been specifically synthesised to cover "diverse" chemical space. The majority of these fragments are unique to IOTA – they cannot be purchased elsewhere. Most of the fragments are soluble at 1mM, obeying the Astex "Rule of 3".

Key Organics The BIONETFragment Library Ro3 encompasses 13,027 (June 2012) carefully selected diverse fragments which have been rigorously chosen for their suitability for fragment based screening applications and further chemical elaboration. It has been established that 2479 of these fragments are uniquely available through Bionet. The BIONET Extended Fragment Library: The BIONET Extended Fragment Library comprises 4,439 fragments selected using relaxation of the Ro3 filters, however only one of these softer filters is applied to any one fragment. Examples: Fragment profile A: MW 326, cLogP 2.8, Rtb 2, Hba 2, Hbd 2 Fragment profile B: MW 207, cLogP 1.1, Rtb 4, Hba 3, Hbd 1 There is no overlap between the BIONET Extended Fragment Library and the established BIONET 'Ro3' Library. There is also a Fluoro and a Bromo subset together with a focused library containing 700 Fragments selected for their suitability for Fragment Based Lead Discovery in the areas of CNS drug discovery and Universal target classes.

Life Chemicals Life Chemicals now offer a number of different sets. Zen-Life – highly diverse 500 compounds, checked solubility 200mM DMSO , the criteria applied were significantly more stringent than Ro3.

Diversity Fragments set.  About 3500 compounds Diverse Fragment  Library with checked solubility 200 mM DMSO, selected according to the following criteria:- MW less than 300, - clogP less than 3.  

Fluorine-Based Fragment Library. This highly diversity  library contains 1,300 fluorinated fragments allowing for easier identification of the fragment bound in the active site of a target by the highly sensitive 19F-NMR technique.

There is also a General Fragment Collection  -29,500 in-stock compounds available for immediate delivery.

Maybridge The Maybridge Ro3 2500 Diversity Fragment Library: As the field of Fragment–Based Drug Discovery continues to mature there is an increasing need to gain access to fragments of the highest quality. Built on a pedigree of almost 50 years of heterocycle research, the Maybridge Fragment Range has grown with the technology over the past 7 years as structure based techniques become more central to the drug discovery process and many successful fragment screening programmes have Maybridge Fragments at their heart. The latest addition to the Maybridge Fragment range, is the Maybridge Ro3 2500 Diversity Fragment Library. The library has been engineered to build on the key customer driven features of original Maybridge Ro3 Library, such as Ro3 compliance pharmacophoric enrichment and quality assurance. The Maybridge Ro3 Diversity Library offers both an improved structural diversity profile and experimental solubility data for each of the 2500 members. Key Features Rule of Three (Ro3) compliance Computationally engineered diversity Assured solubility in both DMSO (200mM) and PBS buffer (1mM) Assured quality to ≥95%, including NMR spectra for every compound Chemically “clean” – removal of reactive group whilst retaining “handles” for conjugation and hit evolution. Pharmacophore rich but not too complex

The Maybridge Ro3 Diversity Fragment Library is available in the following formats Entire library with 2,500 compounds: Highly recommended. It provides the highest probability to find a hit. A core set of the entire library with 1,000 compounds: It encompasses the diversity of the entire library. Suitable for rapid and exploratory work. A supplement set of the entire library with 1,500 compounds: for those who have screened the core set. It provides an additional probability to identify more hits. Customised set, a selection of any number of fragments.: our searchable database allows rapid selection of fragments based on substructure and calculated Ro3 parameters.

All Maybridge Fragments are available custom weighed to your requirements in milligram (≥1mg) or micromolar quantities (≥ 5μmol) and have been selected to ensure that they are readily available for re-supply. Full analytical data is supplied with all orders for the Ro3 libraries. Fragment Hopping with Maybridge Fragments One of the key advantages of working with Maybridge Fragments is that Fragment Hopping is facilitated across the entire Maybridge portfolio. Maybridge Building Blocks and Fragments have been developed through a highly structured product innovation strategy allowing the introduction of logical sets of related compounds which benefit from minimal substitution, a key aspect for effective pharmacophore investigation. The Maybridge Fragment Collection Over 30,000 Maybridge compounds assembled to provide convenient access to the extensive Maybridge portfolio when building your own bespoke Fragment screening libraries or searching for Hit analogues. The Collection has been filtered in terms of purity, molecular weight (≤350Da) and removal of inappropriate functionality to allow you complete freedom to design a library to your own specific needs.

There are also the Maybridge Bromo-Fragment Collection: A collection of over 1500 bromine containing Maybridge fragments constructed as an aid to X-ray based fragment screening and the Maybridge Fluoro-Fragment Collection: A set of over 5300 fluorine containing fragments which are a convenient source for 19F NMR based applications

Otava Recently updated, strict structural, substructural and special medicinal chemistry filters were applied for the library preparation. The OTAVA’s Fragment Library, comprising approximately 7129 compounds, has been designed based upon the commonly accepted "Rule-of-Three" and other physicochemical and structural properties. Compounds were filtered on molecular weight (MW <300); number of H-bond donors ≤ 3; hydrophobicity as the calculated octanol/water partition coefficient (cLogP <3); number of rotatable bonds ≤ 3; number of H-bond acceptors ≤ 4 (the increased number of acceptors in the library was applied to satisfy a kinase binding pharmacophore); molecular polar surface area (PSA < 80); calculated aqueous solubility (LogSW > -5) (high aqueous solubility is essential for practical reasons during screening particularly in HCS). .The following compounds were REMOVED from the library:

"All compounds are in stock (20mg min. amount), cherry-picking is available. "

OTAVA offer a Chelator Fragment Library that comprises 575 compounds in total, Chelators demonstrate binding affinities suitable for FBLD screening and provide a diverse range of molecular platforms from which to develop lead compounds. Also, the propensity for chelators to bind metal ions allows for better prediction of their probable binding position within a protein active site in the absence of experimental structural data of the complex. They also offer a Halogen-Enriched Fragment Library that comprises 430 brominated fragments. The library is intended for rapid hit evolution and more effective identification of the fragment bound in the active site of a drug target by X-ray crystallography. OTAVA’s 19F NMR Fluorine-containing Fragment Library contains 976 fragments. All compounds in this library have at least one mono fluoro or mono trifluoromethyl group. 19F NMR screening offers high throughput (potentially thousands of compounds per day) and low fragment concentration that allows to avoid solubility problems.

Prestwick Chemical The Prestwick Fragment Library is composed of 2230 compounds all carefully selected to match in an optimal way the requirements for fragment based screening techniques. The library contains a MW < 300 set of known drugs, together with a perfectly designed collection of new fragments derived from actual drug molecules. These compounds are optimized to exhibit high ‘Rule of three’ compatibility. All compounds are in stock, and are available as a complete Library in powder form, or may be cherry-picked.

Pyxis Pyxis Discovery has designed and synthesized a library of fragments, which are based on scaffolds that are found in existing drugs. These novel and unique fragments are ‘Rule of 3’ compliant, diverse, filtered for undesirable chemistry and have built-in possibilities for follow-up chemistry. The Smart fragment library provides excellent starting points for fragment evolution programs and is suitable for any fragment screening platform. 98% of the fragments are soluble in DMSO at a concentration of 50 mM. Water solubility information is also available.

Reaxense The library contains 1,000 high-quality fragments selected to meet top industry requirements. It provides an optimal, Ro3 complied, diverse set of compounds to be included in your next fragment screen. Full Rule of Three (Ro3) compliance. Compounds with reactive and toxic groups filtered out, high calculated water solubility (LogS > -5), high diversity over the library. Each fragment contains at least 1 aromatic or aliphatic ring, >90% purity, spectra available.

Selcia A 1300 compound library designed to be ‘rule of 3’ compliant, with high degree of diversity and with the added advantage of > 1mM measured solubility. All shown to be >95% purity by LC-MS and NMR. A poster describing the design and profile of the Selcia library I helped design is available here. This library was designed specifically for the CEFrag screening technology and is now available for purchase.

TimTec Fragment-Based Library, FBL, gathers structurally diverse ligands with well suited chemical-physical properties for FBDD screening. Compounds are delivered in dry form in custom milligram or micromolar amounts and as freshly prepared DMSO solution aliquots. One of the preferred concentrations for FBDD is up to 1.5mM with small volume (1-25-30-50uL) per well. Compound selection criteria for FBDD overlaps in chemical-physical properties and screening techniques, yet is more encompassing and specific, than compound selection criteria for the Rule of Three and, so called, Reduced Complexity Criteria.

Vistas-M labs Designed collection of 8329 Fragments complied on the basis of Rule 3 and other proprietary filters.

Zenobia In general, the 2 screening libraries contain ~300 compounds and have been optimized to cover as much diversity space as possible given the target class restrictions.

If you are building up a collection from commercial suppliers then it is worth reading the Fragment Collection Profiles page.

Fluorine Containing Fragments

A publication by John B. Jordon et al (J. Med. Chem, 2012, 55, 678-687) DOI hdescribes 19F NMR fragment screening used as a very efficient tool for rapid and sensitive detection of fragment hits. They report that fragment screening with a simple one-dimensional 19F NMR experiment (with 1H decoupling) is significantly faster and in many ways more robust than traditional 1H NMR screening. Several companies have now compiled fluorine containing libraries.

The table below compares each of the libraries with each other to examine the degree of overlap between the libraries. The numbers in red are the number of unique compounds in each library.

Octava Maybridge LifeChemicals KeyOrganics Enamine
Octava 976 48 110 23 91
Maybridge 48 5225 35 56 59
LifeChemicals 110 35 3904 29 70
KeyOrganics 23 56 29 1286 28
Enamine 91 59 70 28 5666

Although available fluorine fragment space is smaller than the complete available fragments, there is surprisingly little overlap between the libraries.

Updated 3 February 2017