Thursday, October 22, 2020

Molecule highlighting and R-group decomposition

This one was inspired by a conversation that happened at the 2020 RDKit (virtual) UGM.

During Dominique Sydow's presentation she showed some pictures of molecules with some regions of the molecule highlighted (in her case to indicate which kinase pocket they interact with). Dominique had created the images by hand, but I wanted to explore what's possible using the 2020.09 RDKit release.

What this post is going to demonstrate is doing R-group decomposition (RGD) on a set of molecules that share a common scaffold, generating coordinates for those molecules that are aligned to the scaffold, and generating images of the molecules where the R groups are colored to make them easy to pick out.

The final images we create will look like this:

image.png

The rest of this post will go through the steps to create images like this.

Let's get started

In [1]:
from rdkit import Chem
from rdkit.Chem import Draw
from rdkit.Chem.Draw import IPythonConsole
IPythonConsole.molSize=(450,350)
from rdkit.Chem import rdRGroupDecomposition
from rdkit.Chem import rdqueries
from rdkit.Chem import rdDepictor
from rdkit.Chem.Draw import rdMolDraw2D
from rdkit import Geometry
rdDepictor.SetPreferCoordGen(True)
import pandas as pd

from IPython.display import SVG,Image
from ipywidgets import interact

import rdkit
print(rdkit.__version__)
2020.09.1

Start by reading in the data we will use. This is a collection of ChEMBL compounds with Ki data measured for CDK2. The dataset includes compounds from a number of different documents and, since these are medchem papers, many of the documents contain groups of compounds that share a common scaffold.

In [2]:
df = pd.read_csv('../data/cdk2_rgd_dataset.csv')
df.head()
Out[2]:
assay_id doc_id description assay_organism assay_chembl_id aidx pref_name activity_id molregno standard_relation ... src_id (#1) type relation value units text_value standard_text_value standard_inchi_key canonical_smiles compound_chembl_id
0 50641 17759 Inhibitory activity against human CDK2 (Cyclin... NaN CHEMBL658107 CLD0 Cyclin-dependent kinase 2 265814 68026 > ... 1 Ki > 20.00 uM NaN NaN RPXWUUDZINQPTJ-UHFFFAOYSA-N CNc1nccc(n1)c2sc(C)nc2C CHEMBL46474
1 50641 17759 Inhibitory activity against human CDK2 (Cyclin... NaN CHEMBL658107 CLD0 Cyclin-dependent kinase 2 265817 67880 = ... 1 Ki = 0.14 uM NaN NaN GDZTURHUKDAJGD-UHFFFAOYSA-N Cc1nc(C)c(s1)c2ccnc(Nc3ccc(O)cc3)n2 CHEMBL442957
2 50641 17759 Inhibitory activity against human CDK2 (Cyclin... NaN CHEMBL658107 CLD0 Cyclin-dependent kinase 2 267078 67751 = ... 1 Ki = 6.50 uM NaN NaN CTFDMGIBHFQWKB-UHFFFAOYSA-N Cc1nc(C)c(s1)c2ccnc(N)n2 CHEMBL47302
3 50641 17759 Inhibitory activity against human CDK2 (Cyclin... NaN CHEMBL658107 CLD0 Cyclin-dependent kinase 2 267081 67782 = ... 1 Ki = 1.20 uM NaN NaN HOKDXVAONYXHJK-UHFFFAOYSA-N Cc1nc(C)c(s1)c2ccnc(Nc3ccccc3F)n2 CHEMBL297447
4 50641 17759 Inhibitory activity against human CDK2 (Cyclin... NaN CHEMBL658107 CLD0 Cyclin-dependent kinase 2 267084 67961 = ... 1 Ki = 0.11 uM NaN NaN XNKSRGHGPSHYIW-UHFFFAOYSA-N CNc1nc(C)c(s1)c2ccnc(Nc3cccc(O)c3)n2 CHEMBL44119

5 rows × 28 columns

We pick a group of compounds by selecting all the rows with a given assay ID:

In [3]:
df_doc1 = df[df.assay_chembl_id=='CHEMBL827377']
print(len(df_doc1))
df_doc1.head()
91
Out[3]:
assay_id doc_id description assay_organism assay_chembl_id aidx pref_name activity_id molregno standard_relation ... src_id (#1) type relation value units text_value standard_text_value standard_inchi_key canonical_smiles compound_chembl_id
47 302524 21080 Binding affinity for human cyclin-dependent ki... Homo sapiens CHEMBL827377 CLD0 Cyclin-dependent kinase 2 1438958 305637 > ... 1 Ki > 19.95 uM NaN NaN TWQUOUJLNRGSRZ-UHFFFAOYSA-N Cc1ccc2c(c3ccnc(Nc4cccc(c4)C(F)(F)F)n3)c(nn2n1... CHEMBL182493
48 302524 21080 Binding affinity for human cyclin-dependent ki... Homo sapiens CHEMBL827377 CLD0 Cyclin-dependent kinase 2 1438962 305651 > ... 1 Ki > 19.95 uM NaN NaN CYHPFZLFUXOCJJ-UHFFFAOYSA-N Cc1ccc2c(c3ccnc(Nc4ccc(F)c(F)c4)n3)c(nn2n1)c5c... CHEMBL182326
49 302524 21080 Binding affinity for human cyclin-dependent ki... Homo sapiens CHEMBL827377 CLD0 Cyclin-dependent kinase 2 1439061 305664 > ... 1 Ki > 19.95 uM NaN NaN MYSOMHSTKVRJRA-UHFFFAOYSA-N Cc1ccc2c(c3ccnc(Nc4ccc5OCCOc5c4)n3)c(nn2n1)c6c... CHEMBL183064
50 302524 21080 Binding affinity for human cyclin-dependent ki... Homo sapiens CHEMBL827377 CLD0 Cyclin-dependent kinase 2 1439063 305674 > ... 1 Ki > 19.95 uM NaN NaN VUGNSTAXWJUVEZ-UHFFFAOYSA-N Cc1ccc2c(c3ccnc(Nc4ccc(Cl)c(c4)C(F)(F)F)n3)c(n... CHEMBL361038
51 302524 21080 Binding affinity for human cyclin-dependent ki... Homo sapiens CHEMBL827377 CLD0 Cyclin-dependent kinase 2 1439065 305687 = ... 1 Ki = 3.98 uM NaN NaN BWBMBCPGRIOUNV-UHFFFAOYSA-N C1CC1c2nn3ncccc3c2c4ccnc(Nc5ccccc5)n4 CHEMBL362296

5 rows × 28 columns

Look at some of the compounds:

In [4]:
rdDepictor.SetPreferCoordGen(True)
smis = df_doc1['canonical_smiles']
cids = list(df_doc1.compound_chembl_id)
ms = [Chem.MolFromSmiles(x) for x in smis]
for m in ms:
    rdDepictor.Compute2DCoords(m)
Draw.MolsToGridImage(ms[:12],legends=cids,molsPerRow=4)
Out[4]:

Define a core. I'm doing this manually and am only specifically labeling four of the seven R-groups in this set of molecules. The others will be labelled automatically by the RGD code.

In [5]:
core = Chem.MolFromSmiles('c1cc(-c2c([*:1])nn3nc([*:2])ccc23)nc(N(c2ccc([*:4])c([*:3])c2))n1')
rdDepictor.SetPreferCoordGen(True)
rdDepictor.Compute2DCoords(core)
core
Out[5]:

Some pre-processing work we need to do:

  • convert the dummy atoms in the scaffold into query atoms that match anything
  • add hydrogens to the molecules
  • select only the subset of molecules which match the core
  • set a property on each atom which is used to track its original index (we use this later in the RGD analysis)
In [6]:
ps = Chem.AdjustQueryParameters.NoAdjustments()
ps.makeDummiesQueries=True
qcore = Chem.AdjustQueryProperties(core,ps)
mhs = [Chem.AddHs(x,addCoords=True) for x in ms]
mms = [x for x in mhs if x.HasSubstructMatch(qcore)]
for m in mms:
    for atom in m.GetAtoms():
        atom.SetIntProp("SourceAtomIdx",atom.GetIdx())
print(len(mhs),len(mms))
91 91

Now do the actual RGD:

In [7]:
rdkit.RDLogger.DisableLog('rdApp.warning')
groups,_ = rdRGroupDecomposition.RGroupDecompose([qcore],mms,asSmiles=False,asRows=True)

This is the function that actually does the work of generating aligned coordinates and creating the image with highlighted R groups

In [8]:
from collections import defaultdict

def highlight_rgroups(mol,row,core,width=350,height=200,
                      fillRings=True,legend="",
                      sourceIdxProperty="SourceAtomIdx",
                      lbls=('R1','R2','R3','R4')):
    # copy the molecule and core
    mol = Chem.Mol(mol)
    core = Chem.Mol(core)

    # -------------------------------------------
    # include the atom map numbers in the substructure search in order to 
    # try to ensure a good alignment of the molecule to symmetric cores
    for at in core.GetAtoms():
        if at.GetAtomMapNum():
            at.ExpandQuery(rdqueries.IsotopeEqualsQueryAtom(200+at.GetAtomMapNum()))
            
    for lbl in row:
        if lbl=='Core':
            continue
        rg = row[lbl]
        for at in rg.GetAtoms():
            if not at.GetAtomicNum() and at.GetAtomMapNum() and \
            at.HasProp('dummyLabel') and at.GetProp('dummyLabel')==lbl:
                # attachment point. the atoms connected to this
                # should be from the molecule
                for nbr in at.GetNeighbors():
                    if nbr.HasProp(sourceIdxProperty):
                        mAt = mol.GetAtomWithIdx(nbr.GetIntProp(sourceIdxProperty))
                        if mAt.GetIsotope():
                            mAt.SetIntProp('_OrigIsotope',mAt.GetIsotope())
                        mAt.SetIsotope(200+at.GetAtomMapNum())
    # remove unmapped hs so that they don't mess up the depiction
    rhps = Chem.RemoveHsParameters()
    rhps.removeMapped = False
    tmol = Chem.RemoveHs(mol,rhps)
    rdDepictor.GenerateDepictionMatching2DStructure(tmol,core)

    oldNewAtomMap={}
    # reset the original isotope values and account for the fact that
    # removing the Hs changed atom indices
    for i,at in enumerate(tmol.GetAtoms()):
        if at.HasProp(sourceIdxProperty):
            oldNewAtomMap[at.GetIntProp(sourceIdxProperty)] = i
            if at.HasProp("_OrigIsotope"):
                at.SetIsotope(at.GetIntProp("_OrigIsotope"))
                at.ClearProp("_OrigIsotope")
            else:
                at.SetIsotope(0)
      
    # ------------------
    #  set up our colormap
    #   the three choices here are all "colorblind" colormaps
    
    # "Tol" colormap from https://davidmathlogic.com/colorblind
    colors = [(51,34,136),(17,119,51),(68,170,153),(136,204,238),(221,204,119),(204,102,119),(170,68,153),(136,34,85)]
    # "IBM" colormap from https://davidmathlogic.com/colorblind
    colors = [(100,143,255),(120,94,240),(220,38,127),(254,97,0),(255,176,0)]
    # Okabe_Ito colormap from https://jfly.uni-koeln.de/color/
    colors = [(230,159,0),(86,180,233),(0,158,115),(240,228,66),(0,114,178),(213,94,0),(204,121,167)]
    for i,x in enumerate(colors):
        colors[i] = tuple(y/255 for y in x)
  
    #----------------------
    # Identify and store which atoms, bonds, and rings we'll be highlighting
    highlightatoms = defaultdict(list)
    highlightbonds = defaultdict(list)
    atomrads = {}
    widthmults = {}

    rings = []
    for i,lbl in enumerate(lbls):    
        color = colors[i%len(colors)]
        rquery = row[lbl]
        Chem.GetSSSR(rquery)
        rinfo = rquery.GetRingInfo()
        for at in rquery.GetAtoms():
            if at.HasProp(sourceIdxProperty):
                origIdx = oldNewAtomMap[at.GetIntProp(sourceIdxProperty)]
                highlightatoms[origIdx].append(color)
                atomrads[origIdx] = 0.4
        if fillRings:
            for aring in rinfo.AtomRings():
                tring = []
                allFound = True
                for aid in aring:
                    at = rquery.GetAtomWithIdx(aid)
                    if not at.HasProp(sourceIdxProperty):
                        allFound = False
                        break
                    tring.append(oldNewAtomMap[at.GetIntProp(sourceIdxProperty)])
                if allFound:
                    rings.append((tring,color))
        for qbnd in rquery.GetBonds():
            batom = qbnd.GetBeginAtom()
            eatom = qbnd.GetEndAtom()
            if batom.HasProp(sourceIdxProperty) and eatom.HasProp(sourceIdxProperty):
                origBnd = tmol.GetBondBetweenAtoms(oldNewAtomMap[batom.GetIntProp(sourceIdxProperty)],
                                                 oldNewAtomMap[eatom.GetIntProp(sourceIdxProperty)])
                bndIdx = origBnd.GetIdx()
                highlightbonds[bndIdx].append(color)
                widthmults[bndIdx] = 2

    d2d = rdMolDraw2D.MolDraw2DCairo(width,height)
    dos = d2d.drawOptions()
    dos.useBWAtomPalette()
                
    #----------------------
    # if we are filling rings, go ahead and do that first so that we draw
    # the molecule on top of the filled rings
    if fillRings and rings:
        # a hack to set the molecule scale
        d2d.DrawMoleculeWithHighlights(tmol,legend,dict(highlightatoms),
                                       dict(highlightbonds),
                                       atomrads,widthmults)
        d2d.ClearDrawing()
        conf = tmol.GetConformer()
        for (aring,color) in rings:
            ps = []
            for aidx in aring:
                pos = Geometry.Point2D(conf.GetAtomPosition(aidx))
                ps.append(pos)
            d2d.SetFillPolys(True)
            d2d.SetColour(color)
            d2d.DrawPolygon(ps)
        dos.clearBackground = False

    #----------------------
    # now draw the molecule, with highlights:
    d2d.DrawMoleculeWithHighlights(tmol,legend,dict(highlightatoms),dict(highlightbonds),
                                   atomrads,widthmults)
    d2d.FinishDrawing()
    png = d2d.GetDrawingText()
    return png

Interactively try that out on all the molecules in our set:

In [9]:
@interact(idx=range(0,len(ms)))
def draw_it(idx=0):
    m = mms[idx]
    row = groups[idx]
    return Image(highlight_rgroups(m,row,qcore,lbls=('R1','R2','R3','R4')))

It would be cool to do see multiple molecules at once. Unforunately DrawMolsToGridImage() doesn't support the multiple highlighting we're doing here (we decided that the API for that would just be too complex; this may change in the future if we can figure out a sensible API for it), so we have to manually combine the images. Fortunately the pillow package makes that easy:

In [10]:
from PIL import Image as pilImage
from io import BytesIO

def draw_multiple(ms,groups,qcore,lbls,legends=None,nPerRow=4,subImageSize=(250,200)):
    nRows = len(ms)//nPerRow
    if len(ms)%nPerRow:
        nRows+=1
    nCols = nPerRow
    imgSize = (subImageSize[0]*nCols,subImageSize[1]*nRows)
    res = pilImage.new('RGB',imgSize)
    
    for i,m in enumerate(ms):
        col = i%nPerRow
        row = i//nPerRow
        if legends:
            legend = legends[i]
        else:
            legend = ''
        png = highlight_rgroups(m,groups[i],qcore,lbls=lbls,legend=legend,
                               width=subImageSize[0],height=subImageSize[1])
        bio = BytesIO(png)
        img = pilImage.open(bio)
        res.paste(img,box=(col*subImageSize[0],row*subImageSize[1]))
    bio = BytesIO()
    res.save(bio,format='PNG')
    return bio.getvalue()

Now let's look at the first 16 molecules in the dataset:

In [11]:
Image(draw_multiple(mms[:16],groups,qcore,('R1','R2','R3','R4'),subImageSize=(300,250)))
Out[11]:

Repeat that analysis with the compounds from another document just to make sure we did everything sufficiently generally:

In [12]:
df_doc2 = df[df.assay_chembl_id=='CHEMBL658107']
print(len(df_doc2))
df_doc2.head()
33
Out[12]:
assay_id doc_id description assay_organism assay_chembl_id aidx pref_name activity_id molregno standard_relation ... src_id (#1) type relation value units text_value standard_text_value standard_inchi_key canonical_smiles compound_chembl_id
0 50641 17759 Inhibitory activity against human CDK2 (Cyclin... NaN CHEMBL658107 CLD0 Cyclin-dependent kinase 2 265814 68026 > ... 1 Ki > 20.00 uM NaN NaN RPXWUUDZINQPTJ-UHFFFAOYSA-N CNc1nccc(n1)c2sc(C)nc2C CHEMBL46474
1 50641 17759 Inhibitory activity against human CDK2 (Cyclin... NaN CHEMBL658107 CLD0 Cyclin-dependent kinase 2 265817 67880 = ... 1 Ki = 0.14 uM NaN NaN GDZTURHUKDAJGD-UHFFFAOYSA-N Cc1nc(C)c(s1)c2ccnc(Nc3ccc(O)cc3)n2 CHEMBL442957
2 50641 17759 Inhibitory activity against human CDK2 (Cyclin... NaN CHEMBL658107 CLD0 Cyclin-dependent kinase 2 267078 67751 = ... 1 Ki = 6.50 uM NaN NaN CTFDMGIBHFQWKB-UHFFFAOYSA-N Cc1nc(C)c(s1)c2ccnc(N)n2 CHEMBL47302
3 50641 17759 Inhibitory activity against human CDK2 (Cyclin... NaN CHEMBL658107 CLD0 Cyclin-dependent kinase 2 267081 67782 = ... 1 Ki = 1.20 uM NaN NaN HOKDXVAONYXHJK-UHFFFAOYSA-N Cc1nc(C)c(s1)c2ccnc(Nc3ccccc3F)n2 CHEMBL297447
4 50641 17759 Inhibitory activity against human CDK2 (Cyclin... NaN CHEMBL658107 CLD0 Cyclin-dependent kinase 2 267084 67961 = ... 1 Ki = 0.11 uM NaN NaN XNKSRGHGPSHYIW-UHFFFAOYSA-N CNc1nc(C)c(s1)c2ccnc(Nc3cccc(O)c3)n2 CHEMBL44119

5 rows × 28 columns

In [13]:
smis = df_doc2['canonical_smiles']
cids = list(df_doc2.compound_chembl_id)
ms = [Chem.MolFromSmiles(x) for x in smis]
for m in ms:
    rdDepictor.Compute2DCoords(m)
Draw.MolsToGridImage(ms[:12],legends=cids,molsPerRow=4)
Out[13]:
In [14]:
core = Chem.MolFromSmiles('Cc1nc([*:3])sc1-c1ccnc(N([*:1])[*:2])n1')
ps = Chem.AdjustQueryParameters.NoAdjustments()
ps.makeDummiesQueries=True
qcore = Chem.AdjustQueryProperties(core,ps)
mhs = [Chem.AddHs(x,addCoords=True) for x in ms]
mms = [x for x in mhs if x.HasSubstructMatch(qcore)]
for m in mms:
    for atom in m.GetAtoms():
        atom.SetIntProp("SourceAtomIdx",atom.GetIdx())
print(len(mhs),len(mms))
rdDepictor.SetPreferCoordGen(True)
rdDepictor.Compute2DCoords(qcore)
qcore
33 33
Out[14]:
In [15]:
rdkit.RDLogger.DisableLog('rdApp.warning')
groups,_ = rdRGroupDecomposition.RGroupDecompose([qcore],mms,asSmiles=False,asRows=True)
In [16]:
@interact(idx=range(0,len(mms)))
def draw_it(idx=0):
    m = mms[idx]
    row = groups[idx]
    return Image(highlight_rgroups(m,row,qcore,lbls=('R1','R2','R3')))
In [17]:
Image(draw_multiple(mms[:12],groups,qcore,('R1','R2','R3'),subImageSize=(300,250)))
Out[17]:
In [18]:
df_doc3 = df[df.assay_chembl_id=='CHEMBL3101313']
print(len(df_doc3))
df_doc3.head()
25
Out[18]:
assay_id doc_id description assay_organism assay_chembl_id aidx pref_name activity_id molregno standard_relation ... src_id (#1) type relation value units text_value standard_text_value standard_inchi_key canonical_smiles compound_chembl_id
1129 1281340 76402 Displacement of B-Alexa-Fluor647 from CDK2 (un... Homo sapiens CHEMBL3101313 CLD0 Cyclin-dependent kinase 2 13859835 1610535 < ... 1 Ki < 0.10 uM NaN NaN USOUMMYIFYDJEI-ZZTDINLMSA-N COC[C@H](Cc1ccc(O)cc1)NC(=O)c2cc(C(=O)O)c3cc(\... CHEMBL3099753
1130 1281340 76402 Displacement of B-Alexa-Fluor647 from CDK2 (un... Homo sapiens CHEMBL3101313 CLD0 Cyclin-dependent kinase 2 13859836 1610534 = ... 1 Ki = 0.10 uM NaN NaN DLJWCYCMLMVSML-FQEVSTJZSA-N COC[C@H](Cc1ccc(O)cc1)NC(=O)c2cc(C(=O)O)c3cc(c... CHEMBL3099752
1131 1281340 76402 Displacement of B-Alexa-Fluor647 from CDK2 (un... Homo sapiens CHEMBL3101313 CLD0 Cyclin-dependent kinase 2 13859837 1610533 = ... 1 Ki = 0.16 uM NaN NaN BHBDKGIDYKROMY-BAJJQUEBSA-N CN(C)C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c2cc(C(=O)O... CHEMBL3099751
1132 1281340 76402 Displacement of B-Alexa-Fluor647 from CDK2 (un... Homo sapiens CHEMBL3101313 CLD0 Cyclin-dependent kinase 2 13859838 1610532 = ... 1 Ki = 0.10 uM NaN NaN IYRLCOILNQBJEJ-ZNOKPGKASA-N CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c2cc(C(=O)O)c3... CHEMBL3099750
1133 1281340 76402 Displacement of B-Alexa-Fluor647 from CDK2 (un... Homo sapiens CHEMBL3101313 CLD0 Cyclin-dependent kinase 2 13859839 1610531 = ... 1 Ki = 0.30 uM NaN NaN DDIHZTFUIFPFOO-OAQYLSRUSA-N CCC[C@H](Cc1ccc(O)cc1)NC(=O)c2cc(C(=O)O)c3cc(c... CHEMBL3099749

5 rows × 28 columns

Finally, do another document, just because it's fun. :-)

In [19]:
smis = df_doc3['canonical_smiles']
cids = list(df_doc3.compound_chembl_id)
ms = [Chem.MolFromSmiles(x) for x in smis]
for m in ms:
    rdDepictor.Compute2DCoords(m)
Draw.MolsToGridImage(ms[:12],legends=cids,molsPerRow=4)
Out[19]:
In [20]:
core = Chem.MolFromSmiles('OC(=O)c1cc(C(=O)NC(C[*:1])[*:2])nc2ccc([*:3])cc12')
ps = Chem.AdjustQueryParameters.NoAdjustments()
ps.makeDummiesQueries=True
qcore = Chem.AdjustQueryProperties(core,ps)
mhs = [Chem.AddHs(x,addCoords=True) for x in ms]
mms = [x for x in mhs if x.HasSubstructMatch(qcore)]
for m in mms:
    for atom in m.GetAtoms():
        atom.SetIntProp("SourceAtomIdx",atom.GetIdx())
print(len(mhs),len(mms))
rdDepictor.SetPreferCoordGen(True)
rdDepictor.Compute2DCoords(qcore)
qcore
25 22
Out[20]:
In [21]:
rdkit.RDLogger.DisableLog('rdApp.warning')
groups,_ = rdRGroupDecomposition.RGroupDecompose([qcore],mms,asSmiles=False,asRows=True)
In [22]:
@interact(idx=range(0,len(mms)))
def draw_it(idx=0):
    m = mms[idx]
    row = groups[idx]
    return Image(highlight_rgroups(m,row,qcore,lbls=('R1','R2','R3')))
In [23]:
Image(draw_multiple(mms[:12],groups,qcore,('R1','R2','R3'),subImageSize=(300,250)))
Out[23]:

An aside here... it would be nice to include legends in these views too, but there's unfortunately a bug in v2020.09.1 that messes up the ring highlights when we do this:

In [25]:
Image(highlight_rgroups(mms[0],groups[0],qcore,lbls=('R1','R2','R3'),legend=cids[0]))
Out[25]:

We will get that fixed for the 2020.09.2 release.

In [ ]:
 

1 comment:

Tel U said...

What does main topic this blog post "Molecule Highlighting and R-Group Decomposition with RDKit" on rdkit.blogspot.com from October 2020 discuss? Tel U