The PDZ domains play key roles in anchoring receptor proteins in the membrane to cytoskeletal components, different intracellular signal transduction pathways and many human diseases are associated with their dysregulation.

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

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

Eighty five human PDZ domains with known 3D structures were divided into fifteen groups on the basis of amino acid alignment and formation of phylogenetic tree: group 1 – ERBB2, WHRN, PZRN3, USH1C, PDZD7, ERBIN, CAD23, TX1B3; group 2 – DLG1, DLG4, ZO1, SYJ2B, CFTR, SNTB2, SCRIB, GOPC; group 3 – AFAD, NEB1, DLG2, DLG3, MPDZ, PARD3, DVL2, PTN13, APC; group 4 – PICK1, RHPN2, LNX1; group 5 – PCLO, RADIL, RIMS2, IL16, RIMS1, MAGIX, SHRM4, RHG21; group 6 – MAGI2, GRIP2, INADL, LIN7B, MPP2; group 7 – APBA1, APBA3; group 8 – CSKP, EM55, GIPC2, MPP5, MPP7, CRUM1; group 9 – ADRB2, RGS12, MAST2, NHRF1, NHRF3, NHRF4, MAST4; group 10 – MAGI1, MAGI3, ARHGB, ARHGC, ANXA2; group 11 – LMO7, RGS3; group 12 – PDLI1, PDLI2, PDLI4, PDLI5, PDLI7, PTN4, NMDE1, LDB3; group 13 – GRASP, CYTIP; group 14 – IL5RA, SDC4, SDCB1, HTRA1; group 15 – ZO2, TIAM1, FRPD1, CXG1, JAM1, PRAX, AHNK2, SDC1.

Superposition of PDZ 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 7 to 45 for each group) were obtained. These models were validated, optimized and the best models were selected.

During pharmacophore screening top-scored compounds that can interact with pocket between carboxylate-binding loop (βA - βB loop) and αB helix of the PDZ domains were selected. At the final stage selected compounds were clustered with the aim to increase diversity of the PDZ Domain Targeted Library.

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