AnchorQuery™ is a specialized pharmacophore search technology that brings interactive virtual screening of novel protein-protein inhibitors to the desktop. Try one of the interactive examples or read the Getting Started guide in the User Manual to search for a custom pharmacophore.
AnchorQuery™ Workflow
Extract PPI inhibitor starting point pharmacophores from PPI structure with
PocketQuery.
Interactive Examples
IL-2 (PDB)
Interleukin-2 plays a key role in the immune system’s response to infection. In this example, the pharmacophore is derived directly from a small molecule that partially mimics the anchor side-chains contained in the quaternary receptor signaling complex (PDB 2B5I).
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XIAP (PDB)
Inhibitor of apoptosis (IAP) proteins inhibit the catalytic activity of caspases. In this complex, theXIAP-BIR3 domain traps caspase-9 in a monomeric state, preventing catalytic activity. A small-molecule inhibitor could potential restore catalytic activity, re-activating the apoptotic pathway.
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p53/MDM2 (PDB)
This interaction is an anti-cancer target. MDM2 negatively regulatesp53, the “guardian of the genome,” and is overexpressed in many human tumors. Inhibitors of p53/MDM2, some of which have progressed to clinical trials, target the MDM2 pocket defined by three anchor side chains of p53.
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HIV GP41 (PDB)
GP41 is a glycoprotein that is instrumental in the fusion of HIV to a host cell. Peptide-based fusion inhibitor drugs, such as enfuvirtide, prevent the complexation of gp41 with gp120. Small-molecule inhibitors target the same pocket in the gp41 trimer.
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NEMO/IKK (PDB)
IKK is an enzyme complex involved in propagating the cellular inflammation response. NEMO associates with unphosphorylated IKK kinase and activates the catalytic activity. Small molecule inhibitors of NEMO/IKK have therapeutic potential for reducing arthritis, asthma, autoimmune disease, and certain cancers.
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EphB2 (PDB)
Ephrins and Eph receptors are components of cell signalling pathways. These interactions play a role in many aspects of cell development, and are also overexpressed in some cancer cells.
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Background
AnchorQuery™ leverages the concept of anchors, amino acid residues that bury a large amount of solvent accessible surface area at the protein-protein interface. Every compound in our multi-component reaction (MCR) accessible virtual library contains an anchor analog, a functional group that is a chemical mimic of a specific amino acid. AnchorQuery™ pharmacophore queries always include an anchor feature in addition to the standard hydrophobic, ionic, and hydrogen bond donors. All non-anchor features are stored relative to a coordinate system defined by the anchor in an efficient spatial index. Pharmacophore searches scale relative to the breadth and complexity of the query, not the size of the database. As a result, full 3D pharmacophore searches can be executed over millions of explicit conformations in a matter of seconds.
