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Libraries for Fragment-Based Drug Discovery

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The fragment-based approach to drug discovery (FBDD) has been established as an efficient tool in the search for new drugs. [1],[2] It has been often used since the late 1990s. [3] Nowadays a few compounds discovered by FBDD are entering the clinic. [4] FBDD has emerged as an alternative approach to traditional lead identification via high-throughput screening (HTS). Unlike HTS, FBDD identifies smaller compounds, the “fragments”, which bind to different parts of a biological target. Given a somewhat low affinity of fragment compounds to biological targets, highly sensitive analytical techniques must be employed to detect their binding. Presently, high-resolution NMR spectroscopy and mass spectrometry as well as X Ray crystallography are routinely used to identify binding efficacy. FBDD has several advantages over HTS.[1],[2] First, FBDD gives a better chance for the final lead compound to have common drug-likeness parameters. [5] Second, FBDD operates with relatively small (few thousands) collection of fragment compounds of which pair wise combinations cover larger chemical space compared with HTS. [6] Third, the high structural diversity of the fragment libraries allows avoiding potential intellectual property conflicts.

In view of the increasing importance of FBDD for pharmaceutical industry, we have designed and synthesized libraries of quality fragments.

The Enamine Fragment Library 2012 was designed by applying “Rule of three” filters of Astex Therapeutics [7] and strict structural filters [8] to the Enamine Screening Collection (1 800 000 compounds). Criteria used in ADME selection are summarized in Table 1. We identified 28 043 compounds meeting the filter 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, having chemical diversity coefficient 0.885. Remaining 26 543 compounds were organized into the Fragment Library.

Chemical diversity of the Enamine Fragment Library is characterized by the rather high value of 0.826.

Table 1. The parameters used in the design of Fragment Library

Parameter Fragment Library
MW, Da 150-300
clogP -2...3
HBA 0...3
HBD 0...3
RotB 0...3
(TPSA), A2 0…60

Besides “Rule of three” setting cut-off values on physical properties another fragment selection criterion by simply counting non-hydrogen (heavy) atoms in molecules is used in FBDD. The number of heavy atoms is thought to correlate with the ADME parameters. Statistical analysis reveals that building blocks suitable for the synthesis of drug like compounds obeying “Rule of five” should consist of up to 20 heavy atoms. In this context Enamine Screening Collection was filtered by the number of heavy atoms (≤20). Compounds containing toxicophores or reactive groups were removed from the filtered set. The obtained set of fragments has outstanding chemical diversity, 0.842. This “simple” fragment library consisting of 126 597 compounds is presently the World largest collection of off the shelf fragments offered by one supplier. Application of the filtering sequence to the database of In-Stock-Tomorrow Building Blocks yielded 467,397 feasible structures that can be prepared through Enamine REAL Database technology in one synthetic step. [9]

You can download data files for the Fragment Library and the Collection of off the shelf fragments, feasible fragment structures are provided upon request. We welcome cherry picking from libraries and can apply any additional filters to make custom selection.

[1] Erlanson, D. A.; McDowell, R. S.; O’Brien, T. Fragment-based drug discovery. J. Med. Chem. 2004, 47, 3463-3482.
[2]Rees, D. C.; Congreve, M.; Murray, C. W.; Carr, R. Fragment-based lead discovery. Nat. Rev. Drug Discovery 2004, 3, 660-672.
[3]Shuker, S. B.; Hajduk, P. J.; Meadows, R. P.; Fesik, S. W. Discovering high-affinity ligands for proteins: SAR by NMR. Science 1996, 274, 1531-1534.
[4]Hajduk, P. J.; Greer, J. A decade of fragment-based drug design: strategic advances and lessons learned. Nat. Rev. Drug Discov. 2007, 6, 211-219.
[5]Lipinski, C. A. et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug. Deliv. Rev. 1997, 23, 3-25.
[6]Lipinski, C. A.; Hopkins, A. Navigating chemical space for biology and medicine. Nature, 2004, 432, 855-861.
[7]Congreve, M. et al. A rule of three for fragment-based lead discovery? Drug Discov. Today 2003, 8, 876-877.
[8]Leadlikeness and structural diversity of synthetic screening libraries. Molecular Diversity 2006, 10, No. 3, 377-388.
[9]A. Shivanyuk, S. V. Ryabukhin, A. V. Bogolubsky, D. N. Mykytenko, A. A. Chupryna, W. Heilman, A. N. Kostyuk, A. A Tolmachev. Supp.Chem.Oggi Chem. Today. 2007, 25, 58-59.

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