This is an updated version of a post. The original version of the notebook can be found in github.

A frequent question that comes up when considering fingerprint similarity is: "What threshold should I use to determine what a neighbor is?" The answer is poorly defined. Of course it depends heavily on the details of the fingerprint, but there's also a very subjective component: you want to pick a low enough threshold that you're sure you won't miss anything, but you don't want to pick up too much noise.

The goal here is to systematically come up with some guidelines that can be used for fingerprints supported within the RDKit. We will do that by looking a similarities between random "drug-like" (MW<600) molecules picked from ChEMBL.

For the analysis, the 25K similarity values are sorted and the values at particular threshold are examined.

There's a fair amount of code and results below, so here's the summary table. To help interpret this: 22500 of the 25000 pairs (90%) have a MACCS keys similarity value less than 0.528.

Fingerprint Metric 70% level 80% level 90% level 95% level 99% level
MACCS Tanimoto 0.431 0.471 0.528 0.575 0.655
Morgan0 (counts) Tanimoto 0.429 0.471 0.525 0.568 0.651
Morgan1 (counts) Tanimoto 0.265 0.293 0.333 0.364 0.429
Morgan2 (counts) Tanimoto 0.181 0.201 0.229 0.252 0.305
Morgan3 (counts) Tanimoto 0.141 0.156 0.178 0.196 0.238
Morgan0 (bits) Tanimoto 0.435 0.475 0.529 0.571 0.656
Morgan1 (bits) Tanimoto 0.273 0.301 0.341 0.371 0.434
Morgan2 (bits) Tanimoto 0.197 0.217 0.246 0.269 0.322
Morgan3 (bits) Tanimoto 0.165 0.181 0.203 0.222 0.264
FeatMorgan0 (counts) Tanimoto 0.583 0.630 0.690 0.737 0.818
FeatMorgan1 (counts) Tanimoto 0.390 0.425 0.474 0.511 0.581
FeatMorgan2 (counts) Tanimoto 0.272 0.298 0.333 0.364 0.424
FeatMorgan3 (counts) Tanimoto 0.209 0.228 0.256 0.279 0.328
FeatMorgan0 (bits) Tanimoto 0.583 0.630 0.690 0.737 0.818
FeatMorgan1 (bits) Tanimoto 0.395 0.429 0.477 0.514 0.585
FeatMorgan2 (bits) Tanimoto 0.284 0.310 0.347 0.376 0.434
FeatMorgan3 (bits) Tanimoto 0.228 0.248 0.276 0.299 0.349
RDKit 4 (bits) Tanimoto 0.209 0.239 0.285 0.325 0.426
RDKit 5 (bits) Tanimoto 0.197 0.219 0.253 0.287 0.368
RDKit 6 (bits) Tanimoto 0.230 0.250 0.280 0.308 0.369
RDKit 7 (bits) Tanimoto 0.313 0.346 0.389 0.429 0.507
linear RDKit 4 (bits) Tanimoto 0.225 0.258 0.309 0.354 0.462
linear RDKit 5 (bits) Tanimoto 0.198 0.225 0.269 0.309 0.404
linear RDKit 6 (bits) Tanimoto 0.187 0.210 0.246 0.282 0.365
linear RDKit 7 (bits) Tanimoto 0.182 0.203 0.234 0.264 0.337
Atom Pairs (counts) Tanimoto 0.180 0.204 0.237 0.265 0.325
Torsions (counts) Tanimoto 0.107 0.130 0.165 0.194 0.266
Atom Pairs (bits) Tanimoto 0.275 0.301 0.335 0.363 0.415
Torsions (bits) Tanimoto 0.133 0.155 0.188 0.219 0.288
Avalon 512 (bits) Tanimoto 0.369 0.407 0.461 0.505 0.575
Avalon 1024 (bits) Tanimoto 0.269 0.297 0.340 0.375 0.449
Avalon 512 (counts) Tanimoto 0.300 0.333 0.379 0.418 0.491
Avalon 1024 (counts) Tanimoto 0.267 0.299 0.344 0.384 0.462
from rdkit import Chem
from rdkit.Chem import rdMolDescriptors
from rdkit.Avalon import pyAvalonTools
from rdkit.Chem import Draw
from rdkit.Chem.Draw import IPythonConsole
from rdkit import rdBase
from rdkit import DataStructs
from collections import defaultdict
import pickle,random,gzip
print(rdBase.rdkitVersion)
import time
print(time.asctime())
%pylab inline
2021.03.1
Tue May 18 06:44:23 2021
Populating the interactive namespace from numpy and matplotlib
/home/glandrum/miniconda3/envs/rdkit_blog/lib/python3.9/site-packages/IPython/core/magics/pylab.py:159: UserWarning: pylab import has clobbered these variables: ['random']
`%matplotlib` prevents importing * from pylab and numpy
  warn("pylab import has clobbered these variables: %s"  % clobbered +

Read in the data

We're using the set of 25K reference pairs generated in an earlier post: http://rdkit.blogspot.ch/2013/10/building-similarity-comparison-set-goal.html

As a quick reminder: these are pairs of molecules taken from ChEMBL with MW<600 and a count-based MFP0 similarity of at least 0.7 to each other.

ind = [x.split() for x in gzip.open('../data/chembl16_25K.pairs.txt.gz')]
ms1 = []
ms2 = []
for i,row in enumerate(ind):
    m1 = Chem.MolFromSmiles(row[1])
    ms1.append((row[0],m1))
    m2 = Chem.MolFromSmiles(row[3])
    ms2.append((row[2],m2))
    

Those pairs are related to each other, but we want random pairs, so shuffle the second list:

random.seed(23)
random.shuffle(ms2)
try:
    import ipyparallel as ipp
    rc = ipp.Client()
    dview = rc[:]
    dview.execute('from rdkit import Chem')
    dview.execute('from rdkit import Descriptors')
    dview.execute('from rdkit.Chem import rdMolDescriptors')
    dview.execute('from rdkit.Avalon import pyAvalonTools')
except:
    print("could not use ipyparallel")
    dview = None
    
def compareFPs(ms1,ms2,fpfn,fpName):
    if dview is not None:
        fps = dview.map_sync(lambda x:fpfn(x[1]),ms1)
        fp2s = dview.map_sync(lambda x:fpfn(x[1]),ms2)
    else:
        fps = [fpfn(x[1]) for x in ms1]
        fp2s = [fpfn(x[1]) for x in ms2]
    sims = [DataStructs.TanimotoSimilarity(x,y) for x,y in zip(fps,fp2s)]
    sl = sorted(sims)
    np = len(sl)
    with open('fp_results.txt','a+') as outf:
        outf.write(f'<tr><td>{fpName}</td><td>Tanimoto</td>\n')
        for bin in (.7,.8,.9,.95,.99):
            simv = sl[int(bin*np)]
            print( bin,simv)
            outf.write(f'  <td>{simv:.3f}</td>\n')
        outf.write('</tr>')
    hist(sims,bins=20)
    xlabel(fpName)
    

MACCS

compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetMACCSKeysFingerprint(x),"MACCS")
0.7 0.4305555555555556
0.8 0.47058823529411764
0.9 0.5283018867924528
0.95 0.575
0.99 0.6551724137931034

Morgan FPs

count based

compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetMorganFingerprint(x,0),"Morgan0 (counts)")
0.7 0.42857142857142855
0.8 0.47058823529411764
0.9 0.525
0.95 0.5675675675675675
0.99 0.6511627906976745
compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetMorganFingerprint(x,1),"Morgan1 (counts)")
0.7 0.2653061224489796
0.8 0.2926829268292683
0.9 0.3333333333333333
0.95 0.36363636363636365
0.99 0.42857142857142855
compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetMorganFingerprint(x,2),"Morgan2 (counts)")
0.7 0.18110236220472442
0.8 0.20125786163522014
0.9 0.22916666666666666
0.95 0.2523364485981308
0.99 0.304635761589404
compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetMorganFingerprint(x,3),"Morgan3 (counts)")
0.7 0.140625
0.8 0.1557377049180328
0.9 0.17751479289940827
0.95 0.19607843137254902
0.99 0.23841059602649006

bit-vector based

compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetHashedMorganFingerprint(x,0,1024),"Morgan0 (bits)")
0.7 0.43478260869565216
0.8 0.475
0.9 0.5294117647058824
0.95 0.5714285714285714
0.99 0.65625
compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetHashedMorganFingerprint(x,1,1024),"Morgan1 (bits)")
0.7 0.2727272727272727
0.8 0.30120481927710846
0.9 0.34065934065934067
0.95 0.37142857142857144
0.99 0.4342105263157895
compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetHashedMorganFingerprint(x,2,1024),"Morgan2 (bits)")
0.7 0.19708029197080293
0.8 0.2169811320754717
0.9 0.24603174603174602
0.95 0.2689655172413793
0.99 0.3217391304347826
compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetHashedMorganFingerprint(x,3,1024),"Morgan3 (bits)")
0.7 0.16477272727272727
0.8 0.18072289156626506
0.9 0.20261437908496732
0.95 0.2222222222222222
0.99 0.26356589147286824

FeatMorgan

count based

compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetMorganFingerprint(x,0,useFeatures=True),"FeatMorgan0 (counts)")
0.7 0.5833333333333334
0.8 0.6296296296296297
0.9 0.6896551724137931
0.95 0.7368421052631579
0.99 0.8181818181818182
compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetMorganFingerprint(x,1,useFeatures=True),"FeatMorgan1 (counts)")
0.7 0.3902439024390244
0.8 0.42528735632183906
0.9 0.47368421052631576
0.95 0.5106382978723404
0.99 0.5813953488372093
compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetMorganFingerprint(x,2,useFeatures=True),"FeatMorgan2 (counts)")
0.7 0.272
0.8 0.29770992366412213
0.9 0.3333333333333333
0.95 0.36363636363636365
0.99 0.424
compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetMorganFingerprint(x,3,useFeatures=True),"FeatMorgan3 (counts)")
0.7 0.2087378640776699
0.8 0.22818791946308725
0.9 0.2558139534883721
0.95 0.2785714285714286
0.99 0.3275862068965517

bit vectors

compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetHashedMorganFingerprint(x,0,1024,useFeatures=True),"FeatMorgan0 (bits)")
0.7 0.5833333333333334
0.8 0.6296296296296297
0.9 0.6896551724137931
0.95 0.7368421052631579
0.99 0.8181818181818182
compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetHashedMorganFingerprint(x,1,1024,useFeatures=True),"FeatMorgan1 (bits)")
0.7 0.39473684210526316
0.8 0.42857142857142855
0.9 0.4772727272727273
0.95 0.5142857142857142
0.99 0.5849056603773585
compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetHashedMorganFingerprint(x,2,1024,useFeatures=True),"FeatMorgan2 (bits)")
0.7 0.28368794326241137
0.8 0.30973451327433627
0.9 0.3469387755102041
0.95 0.37606837606837606
0.99 0.43434343434343436
compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetHashedMorganFingerprint(x,3,1024,useFeatures=True),"FeatMorgan3 (bits)")
0.7 0.22807017543859648
0.8 0.24770642201834864
0.9 0.27564102564102566
0.95 0.29901960784313725
0.99 0.3488372093023256

RDKit

Branched (default)

compareFPs(ms1,ms2,lambda x:Chem.RDKFingerprint(x,maxPath=4),"RDKit 4 (bits)")
0.7 0.2094017094017094
0.8 0.23863636363636365
0.9 0.2849462365591398
0.95 0.3254237288135593
0.99 0.4258373205741627
compareFPs(ms1,ms2,lambda x:Chem.RDKFingerprint(x,maxPath=5),"RDKit 5 (bits)")
0.7 0.19672131147540983
0.8 0.21875
0.9 0.2534562211981567
0.95 0.28735632183908044
0.99 0.3682170542635659
compareFPs(ms1,ms2,lambda x:Chem.RDKFingerprint(x,maxPath=6),"RDKit 6 (bits)")
0.7 0.22965641952983726
0.8 0.2502120441051739
0.9 0.28023598820059
0.95 0.30818767249310025
0.99 0.3686382393397524
compareFPs(ms1,ms2,lambda x:Chem.RDKFingerprint(x,maxPath=7),"RDKit 7 (bits)")
0.7 0.3130372492836676
0.8 0.34558303886925795
0.9 0.38909541511771994
0.95 0.4286600496277916
0.99 0.5068903535050928

linear

compareFPs(ms1,ms2,lambda x:Chem.RDKFingerprint(x,maxPath=4,branchedPaths=False),"linear RDKit 4 (bits)")
0.7 0.22456140350877193
0.8 0.25773195876288657
0.9 0.30864197530864196
0.95 0.35403726708074534
0.99 0.46153846153846156
compareFPs(ms1,ms2,lambda x:Chem.RDKFingerprint(x,maxPath=5,branchedPaths=False),"linear RDKit 5 (bits)")
0.7 0.19756838905775076
0.8 0.22549019607843138
0.9 0.2687224669603524
0.95 0.3090909090909091
0.99 0.40425531914893614
compareFPs(ms1,ms2,lambda x:Chem.RDKFingerprint(x,maxPath=6,branchedPaths=False),"linear RDKit 6 (bits)")
0.7 0.18657937806873978
0.8 0.21005917159763313
0.9 0.24612403100775193
0.95 0.2820069204152249
0.99 0.36476426799007444
compareFPs(ms1,ms2,lambda x:Chem.RDKFingerprint(x,maxPath=7,branchedPaths=False),"linear RDKit 7 (bits)")
0.7 0.18204488778054864
0.8 0.20286085825747724
0.9 0.23367198838896952
0.95 0.2640625
0.99 0.33689024390243905

Atom pairs and torsions

count-based

compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetAtomPairFingerprint(x),"Atom Pairs (counts)")
0.7 0.17993630573248406
0.8 0.20386266094420602
0.9 0.23671497584541062
0.95 0.26545454545454544
0.99 0.32547169811320753
compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetTopologicalTorsionFingerprint(x),"Torsions (counts)")
0.7 0.10714285714285714
0.8 0.13
0.9 0.16470588235294117
0.95 0.19387755102040816
0.99 0.26582278481012656

bit vectors

compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetHashedAtomPairFingerprintAsBitVect(x),"Atom Pairs (bits)")
0.7 0.27488151658767773
0.8 0.3008298755186722
0.9 0.3353658536585366
0.95 0.36342042755344417
0.99 0.4146341463414634
compareFPs(ms1,ms2,lambda x:rdMolDescriptors.GetHashedTopologicalTorsionFingerprintAsBitVect(x),"Torsions (bits)")
0.7 0.1326530612244898
0.8 0.1553398058252427
0.9 0.18840579710144928
0.95 0.2191780821917808
0.99 0.2876712328767123

Avalon

compareFPs(ms1,ms2,lambda x:pyAvalonTools.GetAvalonFP(x,512),"Avalon 512 (bits)")
0.7 0.3693379790940767
0.8 0.4074074074074074
0.9 0.46130952380952384
0.95 0.5054347826086957
0.99 0.5749318801089919
compareFPs(ms1,ms2,lambda x:pyAvalonTools.GetAvalonFP(x,1024),"Avalon 1024 (bits)")
0.7 0.26932668329177056
0.8 0.2972972972972973
0.9 0.3402061855670103
0.95 0.3747016706443914
0.99 0.4490909090909091

Avalon Counts

compareFPs(ms1,ms2,lambda x:pyAvalonTools.GetAvalonCountFP(x,512),"Avalon 512 (counts)")
0.7 0.30028063610851263
0.8 0.332624867162593
0.9 0.3787951807228916
0.95 0.4175461741424802
0.99 0.491005291005291
compareFPs(ms1,ms2,lambda x:pyAvalonTools.GetAvalonCountFP(x,1024),"Avalon 1024 (counts)")
0.7 0.26651162790697674
0.8 0.2988505747126437
0.9 0.34438775510204084
0.95 0.3844486589000271
0.99 0.4624173180998196