Enamine Golden Fragment Library

Transcription

1 Enamine Golden Fragment Library 14 March compounds deliverable as entire set or as selected items. Fragment Based Drug Discovery (FBDD) [1,2] demonstrates remarkable results: more than 3 compounds discovered by FBDD have already entered the clinic [3]. The success of FBDDproject strongly depends on quality of the starting library of fragments. Accessibility to a wide variety of novel fragment space opens the way to further development of active molecules with novel chemotypes. To address the growing interest in fragment screening Enamine has designed the Golden Fragment Library which is the most representative and diverse set of fragments available and is characterized by the following features: Novelty The library is selected from Enamine screening and building blocks collections which are continually being updated with drug like structures occupying new chemical space. Diversity Structures of Enamine fragments were analyzed using similarity scoring [4] to identify the most diverse compounds. The diversity coefficient of our Golden Fragment Library is ~.9 so these fragments represent nearly the entire drug-like Enamine fragment space. Unique character The majority of unique chemotypes (Fsp 3 -enriched, spiro-, F-containing compounds, etc, see the Figure 1) resulting from Enamine s longstanding and constantly evolving synthetic experience are included in the library expanding the research outreach of any drug discovery project. 1% correspondence to Rule of three All compounds strictly follow the Rule of three criterion [5] identifying fragments (see the Table 1 for the criteria of selection). Measured Solubility Solubility was measured for all fragments considered for the Golden Set and all compounds included have a minimum solubility of 1mM in PBS for relative solubility >.85. Possibility for further growing ~67 % of the compounds contain different functional groups (amines, carboxylic acids, alcohols, see the Figure 2) giving the possibility for further rapid chemical modifications which accelerates the synthesis of lead-like compounds utilizing fragment screening information. Page 1 of 5

2 Absence of toxic and reactive motifs Toxicity and highly reactive filters were applied (PAINS [6]) to remove all high reactive and toxic motifs. Purity All compounds are greater than 9% pure as confirmed by NMR spectroscopy and LC(GC)- MS data. Availability and further scale-up All compounds are available in stock in >1mg quantities and scale-up is guaranteed. Table 1. Criteria for selection of compounds for Enamine Golden Fragment Library Parameter Enamine Golden Fragment Library MW 14 - HBA 3 HBD 3 RB 3 HACnt 1 21 (92.8 % <19 HA) LogP TPSA 1 Rings 1 4 Aromatic Rings 2 Fused Rings 3 N+O 1 6 Number of Hal 3 Chiral centers 2 Page 2 of 5

3 Figure 1. Representative set of Enamine Golden Fragment Library. The compounds of Enamine Golden Fragment Library are described with 1176 different Bemis-Murcko loose frameworks [7]. As far as each fragment contains at least one ring the structural diversity starting from ring count is described in the Table 2. Figure 2. Chemical and structural characterization of Enamine Golden Fragment Library. Page 3 of 5

4 Table 2. Analysis of structural diversity of Enamine Golden Fragment Library. Ring count Number of Bemis Murcko loose frameworks Examples of frameworks (spiro- & isolated rings) (bridged & fused rings) 15 (spiro- & isolated rings) 3 & 4 25 (bridged & fused rings) Physical chemical profiling of Enamine Golden Fragment Library is summarized on the Figure 3. Page 4 of 5

5 Mol Weight LogP 5 1 -,5,5 1 1,5 2 5 TPSA 5 Relative Solubility in ,86,88,9,92,94,96,98 1 1,2 1,4 Figure 3. Physical chemical profile for Enamine Golden Fragment Library. Due to the novelty, high chemical and structural diversity, measured solubility for each compound the Enamine Golden Fragment Library will be a new and convenient tool for any MedChem project associated with FBDD expanding the research field of drug discovery. [1] C.W. Murray, D.C. Rees The Rise of Fragment-Based Drug Discovery, Nature Chemistry 9, 1(3), [2] D.A. Erlanson Introduction to Fragment-Based Drug Discovery, Top. Curr. Chem. 212, 317, [3] M. Baker Fragment-Based Lead Discovery Grows Up, Nat. Rev. Drug Discovery 213, 12(1), 5-7. [4] P. Baldi, R. Nasi When is Chemical Similarity Significant? The Statistical Distribution of Chemical Similarity Scores and Its Extreme Values, J. Chem. Inf. Model 21, 5(7), [5] M. Congreve, R. Carr, C. Murray, H. Jhoti A Rule of Three for Fragment-Based Lead Discovery, Drug Discov. Today 3, 8(19), [6] 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. 21, 53(7), [7] J.W. Bemis, M.A. Murcko The properties of known drugs. 1. Molecular frameworks, J. Med. Chem. 1996, 39(15), Page 5 of 5