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# Copyright (c) 2013, GlaxoSmithKline Research & Development Ltd.
# All rights reserved.
#
# Redistribution and use in source and binary forms, with or without
# modification, are permitted provided that the following conditions are
# met:
#
# * Redistributions of source code must retain the above copyright
# notice, this list of conditions and the following disclaimer.
# * Redistributions in binary form must reproduce the above
# copyright notice, this list of conditions and the following
# disclaimer in the documentation and/or other materials provided
# with the distribution.
# * Neither the name of GlaxoSmithKline Research & Development Ltd.
# nor the names of its contributors may be used to endorse or promote
# products derived from this software without specific prior written
# permission.
#
# THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS
# "AS IS" AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT
# LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR
# A PARTICULAR PURPOSE ARE DISCLAIMED. IN NO EVENT SHALL THE COPYRIGHT
# OWNER OR CONTRIBUTORS BE LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL,
# SPECIAL, EXEMPLARY, OR CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT
# LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES; LOSS OF USE,
# DATA, OR PROFITS; OR BUSINESS INTERRUPTION) HOWEVER CAUSED AND ON ANY
# THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, OR TORT
# (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE
# OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE.
#
# Created by Jameed Hussain, May 2013
"""
Fragmentation algorithm
-----------------------
identify acyclic bonds
enumerate all single cuts
make sure you chop off more that 1 atom
keeps bits which are >60% query mol
enumerate all double cuts
keeps bits with 1 attachment point (i.e throw middle bit away)
need to be >60% query mol
identify exocyclic bonds
enumerate all single "ring" cuts
Check if it results in more that one component
keep correct bit if >40% query mol
enumerate successful "rings" cuts with an acyclic cut
Check if it results in more that one component
keep correct if >60% query mol
"""
from itertools import combinations
import sys
from rdkit import Chem, DataStructs
from rdkit.Chem import rdqueries
# our default rdkit fingerprinter parameters:
rdkitFpParams = {'maxPath': 5, 'fpSize': 1024, 'nBitsPerHash': 2}
# Considered fragment types
FTYPE_ACYCLIC = 'acyclic'
FTYPE_CYCLIC = 'cyclic'
FTYPE_CYCLIC_ACYCLIC = 'cyclic_and_acyclic'
# Global SMARTS used by the program
# acyclic bond smarts
ACYC_SMARTS = Chem.MolFromSmarts("*!@!=!#*")
# exocyclic/fused exocyclic bond smarts
CYC_SMARTS = Chem.MolFromSmarts("[R1,R2]@[r;!R1]")
# smarts used to find appropriate fragment for
# would use SMARTS: [$([#0][r].[r][#0]),$([#0][r][#0])]
# but RDkit doesn't support component SMARTS in recursive one - $([#0][r].[r][#0])
# hence split into two
cSma1 = Chem.MolFromSmarts("[#0][r].[r][#0]")
cSma2 = Chem.MolFromSmarts("[#0][r][#0]")
dummyAtomQuery = rdqueries.AtomNumEqualsQueryAtom(0)
def delete_bonds(mol, bonds, ftype, hac):
""" Fragment molecule on bonds and reduce to fraggle fragmentation SMILES.
If none exists, returns None """
# Replace the given bonds with attachment points (B1-B2 -> B1-*.*-B2)
bondIdx = [mol.GetBondBetweenAtoms(*bond).GetIdx() for bond in bonds]
modifiedMol = Chem.FragmentOnBonds(mol, bondIdx, dummyLabels=[(0, 0)] * len(bondIdx))
# should be able to get away without sanitising mol as the valencies should be okay
# do not do a full sanitization, but do find rings and calculate valences:
Chem.SanitizeMol(modifiedMol, Chem.SanitizeFlags.SANITIZE_PROPERTIES |
Chem.SanitizeFlags.SANITIZE_SYMMRINGS)
fragments = Chem.GetMolFrags(modifiedMol, asMols=True, sanitizeFrags=False)
return select_fragments(fragments, ftype, hac)
def select_fragments(fragments, ftype, hac):
if ftype == FTYPE_ACYCLIC:
result = []
result_hcount = 0
for fMol in fragments:
nAttachments = len(fMol.GetAtomsMatchingQuery(dummyAtomQuery))
# check if terminal fragment
if nAttachments == 1:
fhac = fMol.GetNumAtoms()
# if the fragment is 2 atoms (or less - includes attachment) it is too small
# to be interesting. This check has the additional benefit
# of pulling out the relevant single cuts as it discards
# fragments where we only chop off a small part of the input cmpd
if fhac > 3:
result.append(Chem.MolToSmiles(fMol))
result_hcount += fhac
# needs to be greater than 60% of parent mol
if result and (result_hcount > 0.6 * hac):
result = '.'.join(result)
else:
result = None
return result
elif ftype == FTYPE_CYCLIC:
# make sure it is 2 components
if len(fragments) != 2:
return None
result = None
for fMol in fragments:
f = Chem.MolToSmiles(fMol)
# check if a valid cut
# needs to be greater 3 heavy atoms and greater than 40% of parent mol
if isValidRingCut(fMol):
result_hcount = fMol.GetNumAtoms()
if (result_hcount > 3) and (result_hcount > 0.4 * hac):
result = f
return result
elif (ftype == FTYPE_CYCLIC_ACYCLIC):
# need to find the fragments which are valid which means they must be:
# Terminal (one attachment point) or valid ring cut
result = []
result_hcount = 0
for fMol in fragments:
nAttachments = len(fMol.GetAtomsMatchingQuery(dummyAtomQuery))
# We need to have a fragment that has 1 or 2 attachment points and that has more than 3 atoms
if nAttachments >= 3:
continue
fhac = fMol.GetNumAtoms()
if fhac <= 3:
continue
if nAttachments == 2:
# check if a valid cut
if isValidRingCut(fMol):
result.append(Chem.MolToSmiles(fMol))
result_hcount += fhac
elif nAttachments == 1:
result.append(Chem.MolToSmiles(fMol))
result_hcount += fhac
# appropriate fragmentation must have 2 components and needs to be greater than 60% of
# parent mol
if len(result) == 2 and result_hcount > 0.6 * hac:
result = '.'.join(result)
else:
result = None
return result
else:
raise NotImplementedError('Invalid fragmentation type {0}'.format(ftype))
def isValidRingCut(mol):
""" to check is a fragment is a valid ring cut, it needs to match the
SMARTS: [$([#0][r].[r][#0]),$([#0][r][#0])] """
# At this point, the molecule requires the identification of rings, so we need to sanitize
Chem.SanitizeMol(mol, Chem.SanitizeFlags.SANITIZE_SYMMRINGS)
return mol.HasSubstructMatch(cSma1) or mol.HasSubstructMatch(cSma2)
def generate_fraggle_fragmentation(mol, verbose=False):
""" Create all possible fragmentations for molecule
>>> q = Chem.MolFromSmiles('COc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)c(OC)c2ccccc12')
>>> fragments = generate_fraggle_fragmentation(q)
>>> fragments = sorted(['.'.join(sorted(s.split('.'))) for s in fragments])
>>> fragments
['*C(=O)NC1CCN(Cc2cc(OC)c3ccccc3c2OC)CC1',
'*C(=O)c1cncc(C)c1.*C1CCN(Cc2cc(OC)c3ccccc3c2OC)CC1',
'*C(=O)c1cncc(C)c1.*Cc1cc(OC)c2ccccc2c1OC',
'*C(=O)c1cncc(C)c1.*c1cc(OC)c2ccccc2c1OC',
'*C1CCN(Cc2cc(OC)c3ccccc3c2OC)CC1',
'*C1CCN(Cc2cc(OC)c3ccccc3c2OC)CC1.*c1cncc(C)c1',
'*Cc1cc(OC)c2ccccc2c1OC.*NC(=O)c1cncc(C)c1',
'*Cc1cc(OC)c2ccccc2c1OC.*c1cncc(C)c1',
'*N1CCC(NC(=O)c2cncc(C)c2)CC1.*c1cc(OC)c2ccccc2c1OC',
'*NC(=O)c1cncc(C)c1.*c1cc(OC)c2ccccc2c1OC',
'*NC1CCN(Cc2cc(OC)c3ccccc3c2OC)CC1',
'*NC1CCN(Cc2cc(OC)c3ccccc3c2OC)CC1.*c1cncc(C)c1',
'*c1c(CN2CCC(NC(=O)c3cncc(C)c3)CC2)cc(OC)c2ccccc12',
'*c1c(OC)cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)c(OC)c1*',
'*c1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)c(OC)c2ccccc12',
'*c1cc(OC)c2ccccc2c1OC.*c1cncc(C)c1']
"""
# query mol heavy atom count
hac = mol.GetNumAtoms()
# find the relevant bonds to break
acyclic_matching_atoms = mol.GetSubstructMatches(ACYC_SMARTS)
cyclic_matching_atoms = mol.GetSubstructMatches(CYC_SMARTS)
if verbose:
print("Matching Atoms:")
print("acyclic matching atoms: ", acyclic_matching_atoms)
print("cyclic matching atoms: ", cyclic_matching_atoms)
# different cuts can give the same fragments
# to use out_fragments to remove them
out_fragments = set()
######################
# Single acyclic Cuts
######################
# loop to generate every single and double cut in the molecule
# single cuts are not required as relevant single cut fragments can be found
# from the double cuts. For explanation see check_fragments method
for bond1, bond2 in combinations(acyclic_matching_atoms, 2):
fragment = delete_bonds(mol, [bond1, bond2], FTYPE_ACYCLIC, hac)
if fragment is not None:
out_fragments.add(fragment)
##################################
# Fused/Spiro exocyclic bond Cuts
##################################
for bond1, bond2 in combinations(cyclic_matching_atoms, 2):
fragment = delete_bonds(mol, [bond1, bond2], FTYPE_CYCLIC, hac)
if fragment is None:
continue
out_fragments.add(fragment)
# now do an acyclic cut with the successful cyclic cut
for abond in acyclic_matching_atoms:
fragment = delete_bonds(mol, [bond1, bond2, abond], FTYPE_CYCLIC_ACYCLIC, hac)
if fragment is not None:
out_fragments.add(fragment)
return sorted(out_fragments)
def atomContrib(subs, mol, tverskyThresh=0.8):
""" atomContrib algorithm
generate fp of query_substructs (qfp)
loop through atoms of smiles
For each atom
Generate partial fp of the atom (pfp)
Find Tversky sim of pfp in qfp
If Tversky < 0.8, mark atom in smiles
Loop through marked atoms
If marked atom in ring - turn all atoms in that ring to * (aromatic) or Sc (aliphatic)
For each marked atom
If aromatic turn to a *
If aliphatic turn to a Sc
Return modified smiles
"""
def partialSimilarity(atomID):
""" Determine similarity for the atoms set by atomID """
# create empty fp
modifiedFP = DataStructs.ExplicitBitVect(1024)
modifiedFP.SetBitsFromList(aBits[atomID])
return DataStructs.TverskySimilarity(subsFp, modifiedFP, 0, 1)
# generate mol object & fp for input mol (we are interested in the bits each atom sets)
pMol = Chem.Mol(mol)
aBits = []
_ = Chem.RDKFingerprint(pMol, atomBits=aBits, **rdkitFpParams)
# generate fp of query_substructs
qsMol = Chem.MolFromSmiles(subs)
subsFp = Chem.RDKFingerprint(qsMol, **rdkitFpParams)
# loop through atoms of smiles get atoms that have a high similarity with substructure
marked = set()
for atom in pMol.GetAtoms():
if partialSimilarity(atom.GetIdx()) < tverskyThresh:
marked.add(atom.GetIdx())
# get rings to change
# If a marked atom is within a ring, mark the whole ring
markRingAtoms = set()
for ring in pMol.GetRingInfo().AtomRings():
if any(ringAtom in marked for ringAtom in ring):
markRingAtoms.update(ring)
marked.update(markRingAtoms)
if marked:
# now mutate the marked atoms
for idx in marked:
if pMol.GetAtomWithIdx(idx).GetIsAromatic():
pMol.GetAtomWithIdx(idx).SetAtomicNum(0)
pMol.GetAtomWithIdx(idx).SetNoImplicit(True)
else:
# gives best sim
pMol.GetAtomWithIdx(idx).SetAtomicNum(21)
# works better but when replace S it fails due to valency
# pMol.GetAtomWithIdx(idx).SetAtomicNum(6)
try:
Chem.SanitizeMol(pMol, sanitizeOps=Chem.SANITIZE_ALL ^ Chem.SANITIZE_KEKULIZE ^
Chem.SANITIZE_SETAROMATICITY)
except Exception:
sys.stderr.write("Can't parse smiles: %s\n" % (Chem.MolToSmiles(pMol)))
pMol = Chem.Mol(mol)
return pMol
modified_query_fps = {}
def compute_fraggle_similarity_for_subs(inMol, qMol, qSmi, qSubs, tverskyThresh=0.8):
qFP = Chem.RDKFingerprint(qMol, **rdkitFpParams)
iFP = Chem.RDKFingerprint(inMol, **rdkitFpParams)
rdkit_sim = DataStructs.TanimotoSimilarity(qFP, iFP)
qm_key = "%s_%s" % (qSubs, qSmi)
if qm_key in modified_query_fps:
qmMolFp = modified_query_fps[qm_key]
else:
qmMol = atomContrib(qSubs, qMol, tverskyThresh)
qmMolFp = Chem.RDKFingerprint(qmMol, **rdkitFpParams)
modified_query_fps[qm_key] = qmMolFp
rmMol = atomContrib(qSubs, inMol, tverskyThresh)
# wrap in a try, catch
try:
rmMolFp = Chem.RDKFingerprint(rmMol, **rdkitFpParams)
fraggle_sim = max(DataStructs.FingerprintSimilarity(qmMolFp, rmMolFp), rdkit_sim)
except Exception:
sys.stderr.write("Can't generate fp for: %s\n" % (Chem.MolToSmiles(rmMol, True)))
fraggle_sim = 0.0
return rdkit_sim, fraggle_sim
def GetFraggleSimilarity(queryMol, refMol, tverskyThresh=0.8):
""" return the Fraggle similarity between two molecules
>>> q = Chem.MolFromSmiles('COc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)c(OC)c2ccccc12')
>>> m = Chem.MolFromSmiles('COc1cc(CN2CCC(NC(=O)c3ccccc3)CC2)c(OC)c2ccccc12')
>>> sim,match = GetFraggleSimilarity(q,m)
>>> sim
0.980...
>>> match
'*C1CCN(Cc2cc(OC)c3ccccc3c2OC)CC1'
>>> m = Chem.MolFromSmiles('COc1cc(CN2CCC(Nc3nc4ccccc4s3)CC2)c(OC)c2ccccc12')
>>> sim,match = GetFraggleSimilarity(q,m)
>>> sim
0.794...
>>> match
'*C1CCN(Cc2cc(OC)c3ccccc3c2OC)CC1'
>>> q = Chem.MolFromSmiles('COc1ccccc1')
>>> sim,match = GetFraggleSimilarity(q,m)
>>> sim
0.347...
>>> match
'*c1ccccc1'
"""
if hasattr(queryMol, '_fraggleDecomp'):
frags = queryMol._fraggleDecomp
else:
frags = generate_fraggle_fragmentation(queryMol)
queryMol._fraggleDecomp = frags
qSmi = Chem.MolToSmiles(queryMol, True)
result = 0.0
bestMatch = None
for frag in frags:
_, fragsim = compute_fraggle_similarity_for_subs(refMol, queryMol, qSmi, frag, tverskyThresh)
if fragsim > result:
result = fragsim
bestMatch = frag
return result, bestMatch
# ------------------------------------
#
# doctest boilerplate
#
def _runDoctests(verbose=None): # pragma: nocover
import doctest
failed, _ = doctest.testmod(optionflags=doctest.ELLIPSIS + doctest.NORMALIZE_WHITESPACE,
verbose=verbose)
sys.exit(failed)
if __name__ == '__main__': # pragma: nocover
_runDoctests()
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