The SH2 (Src Homology 2) domains play key roles in different kinase-mediated intracellular signal transduction pathways and many human diseases are associated with their dysregulation [1-3].

OTAVAchemicals offers a high quality SH2 Domain Targeted Library (1526 compounds in total). It is a special screening collection containing drug-like compounds with predicted affinity to SH2 domains. This library provides an excellent basis for drug discovery projects related with SH2 domains

The SH2 Domain Targeted Library has been designed using pharmacophore modeling approach. General scheme is presented below:

SH2 domains with known 3D structures were divided into seven groups on the basis of amino acid alignment shown in reference 2: group 1 – GRB7, GRB10, GRB14, JAK1, JAK2, MATK, SYK, ZAP70, TYK2, H2SH2D, CSK; group 2 – NCK1, NCK2, PIK3R1, PTPN6, PTPN11, SOCS2, SOCS4, SOCS6, VAV1, VAV2; group 3 – ABL1, ABL2, FYN, GADS, GRB2, HCK, LCK, SLAP2, SRC, BLK, BRK; group 4 – BRDG1, BKS, CRKL, SH3BP2, TENC1, TNS2, PLCG1; group 5 – FER, FES, RASA1, APS, CHN1, SHC1; group 6 – CBLC, STAT1, STAT5A; group 7 – BMX, BTK, SHIP1, SHIP2, TXK, SH2D1A.

Superposition of SH2 domain structures in each group was performed. All possible pharmacophore features that could interact with binding surfaces of these structures were generated. Correct features were selected after clustering. As a result the sets of pharmacophore models (from 2 to 12 for each group) were obtained. These models were validated, optimized and the best models were selected.

There are two major phosphotyrosin-containing peptide binding regions in SH2 domains: phosphotyrosin binding region and specificity recognition region. During pharmacophore screening top-scored compounds that can interact with this two regions were selected. At the final stage selected compounds were clustered with the aim to increase diversity of the SH2 Domain Targeted Library.

The summary of the SH2 Domain Targeted Library characteristics:

References:

1. Diop A, Santorelli D, Malagrinò F, Nardella C, Pennacchietti V, Pagano L, Marcocci L, Pietrangeli P, Gianni S and Toto A. SH2 Domains: Folding, Binding and Therapeutical Approaches. Int J Mol Sci. Vol.23(24), 2022, pp. 15944.
2. Dziyana Kraskouskaya, Eugenia Duodu, Carolynn C. Arpinw and Patrick T. Gunning. Progress towards the development of SH2 domain inhibitors. Chem Soc Rev. Vol. 42(8), 2013, pp. 3337-70.
3. Bernard A. Liu, Karl Jablonowski, Monica Raina, Michael Arce´, Tony Pawson and Piers D. Nash. The Human and Mouse Complement Resource of SH2 Domain Proteins—Establishing the Boundaries of Phosphotyrosine Signaling. Molecular Cell. Vol. 22, 2006, pp. 851-868.

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