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sp3 Rich Fragment Libraries

Download sp3 Rich Fragment Library SDF
Download Enamine sp3 Rich Special Fragment Set SDF

General sp3 Rich Fragment Library

The utilization of fragment based drug discovery (FBDD) approach has already been proved by more than 30 compounds entering the clinic. Among the main focuses of FBDD are sp3-enriched fragments. Since introduction of the concept “Escape from Flatland” in 2009 implying of increase of saturation fraction Fsp3 and presence of (potential) chiral centers in libraries numerous MedChem projects directed on the design and screening of more saturated fragments have been appeared. Recently the improvement of binding selectivity and frequency toward a set of 100 proteins for diverse small molecules with high ratio of sp3-hybridized and stereogenic atoms have been shown.

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14 000 compounds for cherry picking

The library has been created from Enamine HTS & Building Block Collections. Strict “Rule of three” criteria along with high Fsp3 value cutoff were applied as the main feature of library design. All compounds from the library passed through strict MedChem filters and internal Enamine refinement rules. The final set of compounds has been evaluated to exclude simple reagents and trivial chemotypes. Molecular criteria used for the selection are summarized in the table below:

Parameter Range
MW 120 … 300
Heavy atoms 8 … 20
ClogP -3 … 3
Hb Donors 0 … 3
Hb Acceptors 0 … 3
RotBonds 0 … 3
TPSA ≤ 100 Å2
Fsp3 0.4 … 1
Ring Count 1 … 4

Representative compounds from General sp3 Rich Fragment Library

Enamine sp3-enriched Fragments are characterized by high structural and shape diversity including novel compounds with spiro-, bridged, fused rings  and different combination of isolated rings.

Molecular properties  of the Library

List of references
  1. M. Baker Fragment-Based Lead Discovery Grows Up, Nat. Rev. Drug Discovery 2013, 12 (1), 5-7.
  2. F. Lovering, J. Bikker, C. Humblet Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success, J. Med. Chem. 2009, 52 (21), 6752-6756.
  3. A. W. Hung, A. Ramek, Y. Wang, T. Kaya, J. A. Wilson, P. A. Clemons, D. W. Young Route to Three-dimensional Fragments Using Diversity-Oriented Synthesis, PNAS 2011, 108 (17), 6799-6804.
  4. P. A. Clemons, N. E. Bodycombe, H. A. Carrinski, J. A. Wilson, A. F. Shamji, B. K. Wagner, A. N. Koehler, S. L. Schreiber Small Molecules of Different Origins Have Distinct Distributions of Structural Complexity that Correlate with Protein-binding Profiles, PNAS 2010, 107 (44), 18787-18792.
  5. N. C. Trana, H. Dhondta, M. Flipoa, B. Depreza, N. Willanda Synthesis of Functionalized 2-Isoxazolines as Three-dimensional Fragments for Fragment-based Drug Discovery, Tetrahedron Lett. 2015, 56 (27), 4119-4123.
  6. M. Congreve, R. Carr, C. Murray, H. Jhoti A ‘Rule of Three’ for Fragment-Based Lead Discovery, Drug Discov. Today 2003, 8 (19), 876-877.
  7. J.B. Baell, G.A. Holloway New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays, J. Med. Chem. 2010, 53 (7), 2719-2740.

Enamine sp3 Rich Special Fragment Set

Novelty, high chemical and structural diversity of Enamine sp3 Rich Special Fragment Set will make easier any search of new ligands for challenging targets. In response to new trends and high demands to synthetic molecules used in FBDD projects we have created special set of fragments. Considering the needs for new sp3-enriched fragments and expansion of existing purchasable fragment space Enamine designed small and careful selection of fragments from recently synthesized screening compounds and building blocks.

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1 400 compounds

The Set has been compiled mainly from compounds bearing new chemotypes with presence of privileged structural motifs and their modification often saturated or party hydrogenated. Strict “Rule of three” parameters, summarized in the table below, within the criterion Fsp3 > 0.4 and no more than 18 heavy atoms count were applied for initial selection of the fragments. Structural MedChem filters/rules including PAINS and internal Enamine filters subset were also applied. Manual inspection of resulting set and removal of trivial cores, simple reagents as well as poor/overcomplicated pharmacophore compounds resulted in 1 480 high quality fragments subset.  

Parameter Range
MW 140 … 280
Heavy atoms 9 … 18
ClogP -1 … 3
Hb Donors 0 … 3
Hb Acceptors 0 … 3
RotBonds 0 … 3
TPSA < 70 Å2
Chiral centers ≤ 2
Benzene ring ≤ 1

Examples of compounds from Enamine sp3 Rich Special Fragment Library

Enamine Special sp3 Rich Fragments are characterized by high structural diversity including novel compounds with spiro-, bridged and fused rings with diverse and 3D-enriched character.

Molecular properties of Special sp3 Rich Fragments Set

List of references
  1. M. Baker Fragment-Based Lead Discovery Grows Up, Nat. Rev. Drug Discovery 2013, 12(1), 5-7.
  2. F. Lovering, J. Bikker, C. Humblet Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success, J. Med. Chem. 2009, 52 (21), 6752-6756.
  3. A. W. Hung, A. Ramek, Y. Wang, T. Kaya, J. A. Wilson, P. A. Clemons, D. W. Young Route to Three-dimensional Fragments Using Diversity-Oriented Synthesis, PNAS 2011, 108(17), 6799-6804.
  4. P. A. Clemons, N. E. Bodycombe, H. A. Carrinski, J. A. Wilson, A. F. Shamji, B. K. Wagner, A. N. Koehler, S. L. Schreiber Small Molecules of Different Origins Have Distinct Distributions of Structural Complexity that Correlate with Protein-binding Profiles, PNAS 2010, 107 (44), 18787-18792.
  5. N. C. Trana, H. Dhondta, M. Flipoa, B. Depreza, N. Willanda Synthesis of Functionalized 2-Isoxazolines as Three-dimensional Fragments for Fragment-based Drug Discovery, Tetrahedron Lett. 2015, 56 (27), 4119-4123.
  6. M. Congreve, R. Carr, C. Murray, H. Jhoti A ‘Rule of Three’ for Fragment-Based Lead Discovery, Drug Discov. Today 2003, 8 (19), 876-877.
  7. J.B. Baell, G.A. Holloway New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays, J. Med. Chem. 2010, 53 (7), 2719-2740.
  8. J.W. Bemis, M.A. Murcko The properties of known drugs. 1. Molecular frameworks, J. Med. Chem. 1996, 39 (15), 2887-2893.


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