def __init__(self, reaction_smarts):
# Keep smarts, useful for reporting
self.reaction_smarts = reaction_smarts
# Initialize - assigns stereochemistry and fills in missing rct map numbers
self.rxn = initialize_rxn_from_smarts(reaction_smarts)
# Combine template fragments so we can play around with isotopes
self.template_r, self.template_p = get_template_frags_from_rxn(
self.rxn)
# Define molAtomMapNumber->atom dictionary for template rct and prd
self.atoms_rt_map = {a.GetIntProp('molAtomMapNumber'): a \
for a in self.template_r.GetAtoms() if a.HasProp('molAtomMapNumber')}
self.atoms_pt_map = {a.GetIntProp('molAtomMapNumber'): a \
for a in self.template_p.GetAtoms() if a.HasProp('molAtomMapNumber')}
# Call template_atom_could_have_been_tetra to pre-assign value to atom
[
template_atom_could_have_been_tetra(a)
for a in self.template_r.GetAtoms()
]
[
template_atom_could_have_been_tetra(a)
for a in self.template_p.GetAtoms()
]
def __init__(self, reaction_smarts):
# Keep smarts, useful for reporting
self.reaction_smarts = reaction_smarts
# Initialize - assigns stereochemistry and fills in missing rct map numbers
self.rxn = initialize_rxn_from_smarts(reaction_smarts)
# Combine template fragments so we can play around with mapnums
self.template_r, self.template_p = get_template_frags_from_rxn(
self.rxn)
# Define molAtomMapNumber->atom dictionary for template rct and prd
self.atoms_rt_map = {a.GetAtomMapNum(): a \
for a in self.template_r.GetAtoms() if a.GetAtomMapNum()}
self.atoms_pt_map = {a.GetAtomMapNum(): a \
for a in self.template_p.GetAtoms() if a.GetAtomMapNum()}
# Back-up the mapping for the reaction
self.atoms_rt_idx_to_map = {
a.GetIdx(): a.GetAtomMapNum()
for a in self.template_r.GetAtoms()
}
self.atoms_pt_idx_to_map = {
a.GetIdx(): a.GetAtomMapNum()
for a in self.template_p.GetAtoms()
}
# Check consistency (this should not be necessary...)
if any(self.atoms_rt_map[i].GetAtomicNum() != self.atoms_pt_map[i].GetAtomicNum() \
for i in self.atoms_rt_map if i in self.atoms_pt_map):
raise ValueError(
'Atomic identity should not change in a reaction!')
# Call template_atom_could_have_been_tetra to pre-assign value to atom
[
template_atom_could_have_been_tetra(a)
for a in self.template_r.GetAtoms()
]
[
template_atom_could_have_been_tetra(a)
for a in self.template_p.GetAtoms()
]
# Pre-list chiral double bonds (for copying back into outcomes/matching)
self.rt_bond_dirs_by_mapnum = bond_dirs_by_mapnum(self.template_r)
self.pt_bond_dirs_by_mapnum = bond_dirs_by_mapnum(self.template_p)
# Enumerate possible cis/trans...
self.required_rt_bond_defs, self.required_bond_defs_coreatoms = \
enumerate_possible_cistrans_defs(self.template_r)
def __init__(self, reaction_smarts):
# Keep smarts, useful for reporting
self.reaction_smarts = reaction_smarts
# Initialize - assigns stereochemistry and fills in missing rct map numbers
self.rxn = initialize_rxn_from_smarts(reaction_smarts)
# Combine template fragments so we can play around with isotopes
self.template_r, self.template_p = get_template_frags_from_rxn(self.rxn)
# Define molAtomMapNumber->atom dictionary for template rct and prd
self.atoms_rt_map = {a.GetIntProp('molAtomMapNumber'): a \
for a in self.template_r.GetAtoms() if a.HasProp('molAtomMapNumber')}
self.atoms_pt_map = {a.GetIntProp('molAtomMapNumber'): a \
for a in self.template_p.GetAtoms() if a.HasProp('molAtomMapNumber')}
# Call template_atom_could_have_been_tetra to pre-assign value to atom
[template_atom_could_have_been_tetra(a) for a in self.template_r.GetAtoms()]
[template_atom_could_have_been_tetra(a) for a in self.template_p.GetAtoms()]
def rdchiralRun(rxn,
reactants,
keep_mapnums=False,
combine_enantiomers=True,
return_mapped=False):
'''
rxn = rdchiralReaction (rdkit reaction + auxilliary information)
reactants = rdchiralReactants (rdkit mol + auxilliary information)
note: there is a fair amount of initialization (assigning stereochem), most
importantly assigning atom map numbers to the reactant atoms. It is
HIGHLY recommended to use the custom classes for initialization.
'''
# New: reset atom map numbers for templates in case they have been overwritten
# by previous uses of this template!
rxn.reset()
###############################################################################
# Run naive RDKit on ACHIRAL version of molecules
outcomes = rxn.rxn.RunReactants((reactants.reactants_achiral, ))
if PLEVEL >= (1):
print('Using naive RunReactants, {} outcomes'.format(len(outcomes)))
if not outcomes:
return []
###############################################################################
###############################################################################
# Initialize, now that there is at least one outcome
final_outcomes = set()
mapped_outcomes = {}
# We need to keep track of what map numbers correspond to which atoms
# note: all reactant atoms must be mapped, so this is safe
atoms_r = reactants.atoms_r
# Copy reaction template so we can play around with map numbers
template_r, template_p = rxn.template_r, rxn.template_p
# Get molAtomMapNum->atom dictionary for tempalte reactants and products
atoms_rt_map = rxn.atoms_rt_map
# TODO: cannot change atom map numbers in atoms_rt permanently?
atoms_pt_map = rxn.atoms_pt_map
###############################################################################
for outcome in outcomes:
###############################################################################
# Look for new atoms in products that were not in
# reactants (e.g., LGs for a retro reaction)
if PLEVEL >= (2):
print('Processing {}'.format(
str([Chem.MolToSmiles(x, True) for x in outcome])))
unmapped = 900
for m in outcome:
for a in m.GetAtoms():
# Assign map number to outcome based on react_atom_idx
if a.HasProp('react_atom_idx'):
a.SetAtomMapNum(
reactants.idx_to_mapnum(
int(a.GetProp('react_atom_idx'))))
if not a.GetAtomMapNum():
a.SetAtomMapNum(unmapped)
unmapped += 1
if PLEVEL >= 2:
print('Added {} map numbers to product'.format(unmapped - 900))
###############################################################################
###############################################################################
# Check to see if reactants should not have been matched (based on chirality)
# Define map num -> reactant template atom map
atoms_rt = {a.GetAtomMapNum(): atoms_rt_map[a.GetIntProp('old_mapno')] \
for m in outcome for a in m.GetAtoms() if a.HasProp('old_mapno')}
# Set map numbers of reactant template to be consistent with reactant/product molecules
# note: this is okay to do within the loop, because ALL atoms must be matched
# in the templates, so the atommapnum will get overwritten every time
[a.SetAtomMapNum(i) for (i, a) in atoms_rt.items()]
# Make sure each atom matches
# note: this is a little weird because atom_chirality_matches takes three values,
# -1 (both tetra but opposite), 0 (not a match), and +1 (both tetra and match)
# and we only want to continue if they all equal -1 or all equal +1
prev = None
skip_outcome = False
for match in (atom_chirality_matches(atoms_rt[i], atoms_r[i])
for i in atoms_rt):
if match == 0:
if PLEVEL >= 2:
print(
'Chirality violated! Should not have gotten this match'
)
skip_outcome = True
break
elif match == 2: # ambiguous case
continue
elif prev is None:
prev = match
elif match != prev:
if PLEVEL >= 2:
print(
'Part of the template matched reactant chirality, part is inverted! Should not match'
)
skip_outcome = True
break
if skip_outcome:
continue
if PLEVEL >= 2:
print(
'Chirality matches! Just checked with atom_chirality_matches')
# Check bond chirality - iterate through reactant double bonds where
# chirality is specified (or not). atoms defined by map number
skip_outcome = False
for atoms, dirs, is_implicit in reactants.atoms_across_double_bonds:
if all(i in atoms_rt for i in atoms):
# All atoms definining chirality were matched to the reactant template
# So, check if it is consistent with how the template is defined
#...but /=/ should match \=\ since they are both trans...
matched_atom_map_nums = tuple(atoms_rt[i].GetAtomMapNum()
for i in atoms)
# Convert atoms_rt to original template's atom map numbers:
matched_atom_map_nums = tuple(
rxn.atoms_rt_idx_to_map[atoms_rt[i].GetIdx()]
for i in atoms)
if matched_atom_map_nums not in rxn.required_rt_bond_defs:
continue # this can happen in ring openings, for example
dirs_template = rxn.required_rt_bond_defs[
matched_atom_map_nums]
if dirs != dirs_template and \
(BondDirOpposite[dirs[0]], BondDirOpposite[dirs[1]]) != dirs_template and \
not (dirs_template == (BondDir.NONE, BondDir.NONE) and is_implicit):
if PLEVEL >= 5:
print(
'Reactant bond chirality does not match template!')
if PLEVEL >= 5: print('Based on map numbers...')
if PLEVEL >= 5:
print(' rct: {} -> {}'.format(matched_atom_map_nums,
dirs))
if PLEVEL >= 5:
print(' tmp: {} -> {}'.format(matched_atom_map_nums,
dirs_template))
if PLEVEL >= 5:
print(
'skipping this outcome, should not have matched...'
)
skip_outcome = True
break
if skip_outcome:
continue
###############################################################################
###############################################################################
# Convert product(s) to single product so that all
# reactions can be treated as pseudo-intramolecular
# But! check for ring openings mistakenly split into multiple
# This can be diagnosed by duplicate map numbers (i.e., SMILES)
mapnums = [
a.GetAtomMapNum() for m in outcome for a in m.GetAtoms()
if a.GetAtomMapNum()
]
if len(mapnums) != len(set(mapnums)): # duplicate?
if PLEVEL >= 1:
print('Found duplicate mapnums in product - need to stitch')
# need to do a fancy merge
merged_mol = Chem.RWMol(outcome[0])
merged_map_to_id = {
a.GetAtomMapNum(): a.GetIdx()
for a in outcome[0].GetAtoms() if a.GetAtomMapNum()
}
for j in range(1, len(outcome)):
new_mol = outcome[j]
for a in new_mol.GetAtoms():
if a.GetAtomMapNum() not in merged_map_to_id:
merged_map_to_id[
a.GetAtomMapNum()] = merged_mol.AddAtom(a)
for b in new_mol.GetBonds():
bi = b.GetBeginAtom().GetAtomMapNum()
bj = b.GetEndAtom().GetAtomMapNum()
if PLEVEL >= 10:
print(
'stitching bond between {} and {} in stich has chirality {}, {}'
.format(bi, bj, b.GetStereo(), b.GetBondDir()))
if not merged_mol.GetBondBetweenAtoms(
merged_map_to_id[bi], merged_map_to_id[bj]):
merged_mol.AddBond(merged_map_to_id[bi],
merged_map_to_id[bj],
b.GetBondType())
merged_mol.GetBondBetweenAtoms(
merged_map_to_id[bi],
merged_map_to_id[bj]).SetStereo(b.GetStereo())
merged_mol.GetBondBetweenAtoms(
merged_map_to_id[bi],
merged_map_to_id[bj]).SetBondDir(b.GetBondDir())
outcome = merged_mol.GetMol()
if PLEVEL >= 1:
print('Merged editable mol, converted back to real mol, {}'.
format(Chem.MolToSmiles(outcome, True)))
else:
new_outcome = outcome[0]
for j in range(1, len(outcome)):
new_outcome = AllChem.CombineMols(new_outcome, outcome[j])
outcome = new_outcome
if PLEVEL >= 2: print('Converted all outcomes to single molecules')
###############################################################################
###############################################################################
# Figure out which atoms were matched in the templates
# atoms_rt and atoms_p will be outcome-specific.
atoms_pt = {a.GetAtomMapNum(): atoms_pt_map[a.GetIntProp('old_mapno')] \
for a in outcome.GetAtoms() if a.HasProp('old_mapno')}
atoms_p = {
a.GetAtomMapNum(): a
for a in outcome.GetAtoms() if a.GetAtomMapNum()
}
# Set map numbers of product template
# note: this is okay to do within the loop, because ALL atoms must be matched
# in the templates, so the map numbers will get overwritten every time
# This makes it easier to check parity changes
[a.SetAtomMapNum(i) for (i, a) in atoms_pt.items()]
###############################################################################
###############################################################################
# Check for missing bonds. These are bonds that are present in the reactants,
# not specified in the reactant template, and not in the product. Accidental
# fragmentation can occur for intramolecular ring openings
missing_bonds = []
for (i, j, b) in reactants.bonds_by_mapnum:
if i in atoms_p and j in atoms_p:
# atoms from reactant bond show up in product
if not outcome.GetBondBetweenAtoms(atoms_p[i].GetIdx(),
atoms_p[j].GetIdx()):
#...but there is not a bond in the product between those atoms
if i not in atoms_rt or j not in atoms_rt or not template_r.GetBondBetweenAtoms(
atoms_rt[i].GetIdx(), atoms_rt[j].GetIdx()):
# the reactant template did not specify a bond between those atoms (e.g., intentionally destroy)
missing_bonds.append((i, j, b))
if missing_bonds:
if PLEVEL >= 1:
print(
'Product is missing non-reacted bonds that were present in reactants!'
)
outcome = Chem.RWMol(outcome)
rwmol_map_to_id = {
a.GetAtomMapNum(): a.GetIdx()
for a in outcome.GetAtoms() if a.GetAtomMapNum()
}
for (i, j, b) in missing_bonds:
outcome.AddBond(rwmol_map_to_id[i], rwmol_map_to_id[j])
new_b = outcome.GetBondBetweenAtoms(rwmol_map_to_id[i],
rwmol_map_to_id[j])
new_b.SetBondType(b.GetBondType())
new_b.SetBondDir(b.GetBondDir())
new_b.SetIsAromatic(b.GetIsAromatic())
outcome = outcome.GetMol()
atoms_p = {
a.GetAtomMapNum(): a
for a in outcome.GetAtoms() if a.GetAtomMapNum()
}
else:
if PLEVEL >= 3: print('No missing bonds')
###############################################################################
# Now that we've fixed any bonds, connectivity is set. This is a good time
# to udpate the property cache, since all that is left is fixing atom/bond
# stereochemistry.
try:
Chem.SanitizeMol(outcome)
outcome.UpdatePropertyCache()
except ValueError as e:
if PLEVEL >= 1:
print('{}, {}'.format(Chem.MolToSmiles(outcome, True), e))
continue
###############################################################################
# Correct tetra chirality in the outcome
tetra_copied_from_reactants = []
for a in outcome.GetAtoms():
# Participants in reaction core (from reactants) will have old_mapno
# Spectators present in reactants will have react_atom_idx
# ...so new atoms will have neither!
if not a.HasProp('old_mapno'):
# Not part of the reactants template
if not a.HasProp('react_atom_idx'):
# Atoms only appear in product template - their chirality
# should be properly instantiated by RDKit...hopefully...
if PLEVEL >= 4:
print(
'Atom {} created by product template, should have right chirality'
.format(a.GetAtomMapNum()))
else:
if PLEVEL >= 4:
print(
'Atom {} outside of template, copy chirality from reactants'
.format(a.GetAtomMapNum()))
copy_chirality(atoms_r[a.GetAtomMapNum()], a)
if a.GetChiralTag() != ChiralType.CHI_UNSPECIFIED:
tetra_copied_from_reactants.append(a)
else:
# Part of reactants and reaction core
if template_atom_could_have_been_tetra(
atoms_rt[a.GetAtomMapNum()]):
if PLEVEL >= 3:
print(
'Atom {} was in rct template (could have been tetra)'
.format(a.GetAtomMapNum()))
if template_atom_could_have_been_tetra(
atoms_pt[a.GetAtomMapNum()]):
if PLEVEL >= 3:
print(
'Atom {} in product template could have been tetra, too'
.format(a.GetAtomMapNum()))
# Was the product template specified?
if atoms_pt[a.GetAtomMapNum()].GetChiralTag(
) == ChiralType.CHI_UNSPECIFIED:
# No, leave unspecified in product
if PLEVEL >= 3:
print(
'...but it is not specified in product, so destroy chirality'
)
a.SetChiralTag(ChiralType.CHI_UNSPECIFIED)
else:
# Yes
if PLEVEL >= 3:
print('...and product is specified')
# Was the reactant template specified?
if atoms_rt[a.GetAtomMapNum()].GetChiralTag(
) == ChiralType.CHI_UNSPECIFIED:
# No, so the reaction introduced chirality
if PLEVEL >= 3:
print(
'...but reactant template was not, so copy from product template'
)
copy_chirality(atoms_pt[a.GetAtomMapNum()], a)
else:
# Yes, so we need to check if chirality should be preserved or inverted
if PLEVEL >= 3:
print(
'...and reactant template was, too! copy from reactants'
)
copy_chirality(atoms_r[a.GetAtomMapNum()], a)
if atom_chirality_matches(
atoms_pt[a.GetAtomMapNum()],
atoms_rt[a.GetAtomMapNum()]) == -1:
if PLEVEL >= 3:
print(
'but! reactant template and product template have opposite stereochem, so invert'
)
a.InvertChirality()
else:
# Reactant template chiral, product template not - the
# reaction is supposed to destroy chirality, so leave
# unspecified
if PLEVEL >= 3:
print(
'If reactant template could have been ' +
'chiral, but the product template could not, then we dont need '
+
'to worry about specifying product atom chirality'
)
else:
if PLEVEL >= 3:
print(
'Atom {} could not have been chiral in reactant template'
.format(a.GetAtomMapNum()))
if not template_atom_could_have_been_tetra(
atoms_pt[a.GetAtomMapNum()]):
if PLEVEL >= 3:
print(
'Atom {} also could not have been chiral in product template',
a.GetAtomMapNum())
if PLEVEL >= 3:
print(
'...so, copy chirality from reactant instead')
copy_chirality(atoms_r[a.GetAtomMapNum()], a)
if a.GetChiralTag() != ChiralType.CHI_UNSPECIFIED:
tetra_copied_from_reactants.append(a)
else:
if PLEVEL >= 3:
print(
'Atom could/does have product template chirality!'
.format(a.GetAtomMapNum()))
if PLEVEL >= 3:
print(
'...so, copy chirality from product template')
copy_chirality(atoms_pt[a.GetAtomMapNum()], a)
if PLEVEL >= 3: print('New chiral tag {}'.format(a.GetChiralTag()))
if skip_outcome:
if PLEVEL >= 2: print('Skipping this outcome - chirality broken?')
continue
if PLEVEL >= 2:
print('After attempting to re-introduce chirality, outcome = {}'.
format(Chem.MolToSmiles(outcome, True)))
###############################################################################
###############################################################################
# Correct bond directionality in the outcome
for b in outcome.GetBonds():
if b.GetBondType() != BondType.DOUBLE:
continue
# Ring double bonds do not need to be touched(?)
if b.IsInRing():
continue
ba = b.GetBeginAtom()
bb = b.GetEndAtom()
# Is it possible at all to specify this bond?
if ba.GetDegree() == 1 or bb.GetDegree() == 1:
continue
if PLEVEL >= 5:
print('Looking at outcome bond {}={}'.format(
ba.GetAtomMapNum(), bb.GetAtomMapNum()))
if ba.HasProp('old_mapno') and bb.HasProp('old_mapno'):
# Need to rely on templates for bond chirality, both atoms were
# in the reactant template
if PLEVEL >= 5:
print(
'Both atoms in this double bond were in the reactant template'
)
if (ba.GetIntProp('old_mapno'), bb.GetIntProp('old_mapno')) in \
rxn.required_bond_defs_coreatoms:
if PLEVEL >= 5:
print(
'and reactant template *could* have specified the chirality!'
)
if PLEVEL >= 5:
print('..product should be property instantiated')
continue
if PLEVEL >= 5:
print(
'But it was impossible to have specified chirality (e.g., aux C=C for context)'
)
elif not ba.HasProp('react_atom_idx') and not bb.HasProp(
'react_atom_idx'):
# The atoms were both created by the product template, so any bond
# stereochemistry should have been instantiated by the product template
# already...hopefully...otherwise it isn't specific enough?
continue
# Need to copy from reactants, this double bond was simply carried over,
# *although* one of the atoms could have reacted and been an auxilliary
# atom in the reaction, e.g., C/C=C(/CO)>>C/C=C(/C[Br])
if PLEVEL >= 5:
print(
'Restoring cis/trans character of bond {}={} from reactants'
.format(ba.GetAtomMapNum(), bb.GetAtomMapNum()))
# Start with setting the BeginAtom
begin_atom_specified = restore_bond_stereo_to_sp2_atom(
ba, reactants.bond_dirs_by_mapnum)
if not begin_atom_specified:
# don't bother setting other side of bond, since we won't be able to
# fully specify this bond as cis/trans
continue
# Look at other side of the bond now, the EndAtom
end_atom_specified = restore_bond_stereo_to_sp2_atom(
bb, reactants.bond_dirs_by_mapnum)
if not end_atom_specified:
# note: this can happen if C=C/C-N turns into C=C/C=N
if PLEVEL >= 1:
print(reactants.bond_dirs_by_mapnum)
print(ba.GetAtomMapNum())
print(bb.GetAtomMapNum())
print(Chem.MolToSmiles(reactants.reactants, True))
print(Chem.MolToSmiles(outcome, True))
print(
'Uh oh, looks like bond direction is only specified for half of this bond?'
)
###############################################################################
#Keep track of the reacting atoms for later use in grouping
atoms_diff = {
x: atoms_are_different(atoms_r[x], atoms_p[x])
for x in atoms_rt
}
#make tuple of changed atoms
atoms_changed = tuple(
[x for x in atoms_diff.keys() if atoms_diff[x] == True])
mapped_outcome = Chem.MolToSmiles(outcome, True)
if not keep_mapnums:
for a in outcome.GetAtoms():
a.SetAtomMapNum(0)
# Now, check to see if we have destroyed chirality
# this occurs when chirality was not actually possible (e.g., due to
# symmetry) but we had assigned a tetrahedral center originating
# from the reactants.
# ex: SMILES C(=O)1C[C@H](Cl)CCC1
# SMARTS [C:1]-[C;H0;D3;+0:2](-[C:3])=[O;H0;D1;+0]>>[C:1]-[CH2;D2;+0:2]-[C:3]
skip_outcome = False
if len(tetra_copied_from_reactants) > 0:
Chem.AssignStereochemistry(outcome, cleanIt=True, force=True)
for a in tetra_copied_from_reactants:
if a.GetChiralTag() == ChiralType.CHI_UNSPECIFIED:
if PLEVEL >= 2:
print(
'Auxiliary reactant atom was chiral, now is broken -> skip outcome'
)
skip_outcome = True
break
if skip_outcome:
continue
smiles = Chem.MolToSmiles(outcome, True)
smiles_new = canonicalize_outcome_smiles(smiles)
if smiles_new is None:
continue
final_outcomes.add(smiles_new)
mapped_outcomes[smiles_new] = (mapped_outcome, atoms_changed)
###############################################################################
# One last fix for consolidating multiple stereospecified products...
if combine_enantiomers:
final_outcomes = combine_enantiomers_into_racemic(final_outcomes)
###############################################################################
if return_mapped:
return list(final_outcomes), mapped_outcomes
else:
return list(final_outcomes)
def rdchiralRun(rxn, reactants, keep_isotopes=False, combine_enantiomers=True):
'''
rxn = rdchiralReaction (rdkit reaction + auxilliary information)
reactants = rdchiralReactants (rdkit mol + auxilliary information)
note: there is a fair amount of initialization (assigning stereochem), most
importantly assigning isotope numbers to the reactant atoms. It is
HIGHLY recommended to use the custom classes for initialization.
'''
final_outcomes = set()
# We need to keep track of what map numbers
# (i.e., isotopes) correspond to which atoms
# note: all reactant atoms must be mapped, so this is safe
atoms_r = reactants.atoms_r
# Copy reaction template so we can play around with isotopes
template_r, template_p = rxn.template_r, rxn.template_p
# Get molAtomMapNum->atom dictionary for tempalte reactants and products
atoms_rt_map = rxn.atoms_rt_map
atoms_pt_map = rxn.atoms_pt_map
###############################################################################
# Run naive RDKit on ACHIRAL version of molecules
outcomes = rxn.rxn.RunReactants((reactants.reactants_achiral,))
vprint(2, 'Using naive RunReactants, {} outcomes', len(outcomes))
if not outcomes:
return []
###############################################################################
for outcome in outcomes:
###############################################################################
# Look for new atoms in products that were not in
# reactants (e.g., LGs for a retro reaction)
vprint(2, 'Processing {}', str([Chem.MolToSmiles(x, True) for x in outcome]))
unmapped = 900
for m in outcome:
for a in m.GetAtoms():
# Assign "map" number via isotope
if not a.GetIsotope():
a.SetIsotope(unmapped)
unmapped += 1
vprint(2, 'Added {} map numbers to product', unmapped-900)
###############################################################################
###############################################################################
# Check to see if reactants should not have been matched (based on chirality)
# Define isotope -> reactant template atom map
atoms_rt = {a.GetIsotope(): atoms_rt_map[a.GetIntProp('old_mapno')] \
for m in outcome for a in m.GetAtoms() if a.HasProp('old_mapno')}
# Set isotopes of reactant template
# note: this is okay to do within the loop, because ALL atoms must be matched
# in the templates, so the isotopes will get overwritten every time
[a.SetIsotope(i) for (i, a) in atoms_rt.items()]
# Make sure each atom matches
if not all(atom_chirality_matches(atoms_rt[i], atoms_r[i]) for i in atoms_rt):
vprint(2, 'Chirality violated! Should not have gotten this match')
continue
vprint(2, 'Chirality matches! Just checked with atom_chirality_matches')
# Check bond chirality
#TODO: add bond chirality considerations to exclude improper matches
###############################################################################
###############################################################################
# Convert product(s) to single product so that all
# reactions can be treated as pseudo-intramolecular
# But! check for ring openings mistakenly split into multiple
# This can be diagnosed by duplicate map numbers (i.e., SMILES)
isotopes = [a.GetIsotope() for m in outcome for a in m.GetAtoms() if a.GetIsotope()]
if len(isotopes) != len(set(isotopes)): # duplicate?
vprint(1, 'Found duplicate isotopes in product - need to stitch')
# need to do a fancy merge
merged_mol = Chem.RWMol(outcome[0])
merged_iso_to_id = {a.GetIsotope(): a.GetIdx() for a in outcome[0].GetAtoms() if a.GetIsotope()}
for j in range(1, len(outcome)):
new_mol = outcome[j]
for a in new_mol.GetAtoms():
if a.GetIsotope() not in merged_iso_to_id:
merged_iso_to_id[a.GetIsotope()] = merged_mol.AddAtom(a)
for b in new_mol.GetBonds():
bi = b.GetBeginAtom().GetIsotope()
bj = b.GetEndAtom().GetIsotope()
vprint(10, 'stitching bond between {} and {} in stich has chirality {}, {}'.format(
bi, bj, b.GetStereo(), b.GetBondDir()
))
if not merged_mol.GetBondBetweenAtoms(
merged_iso_to_id[bi], merged_iso_to_id[bj]):
merged_mol.AddBond(merged_iso_to_id[bi],
merged_iso_to_id[bj], b.GetBondType())
merged_mol.GetBondBetweenAtoms(
merged_iso_to_id[bi], merged_iso_to_id[bj]
).SetStereo(b.GetStereo())
merged_mol.GetBondBetweenAtoms(
merged_iso_to_id[bi], merged_iso_to_id[bj]
).SetBondDir(b.GetBondDir())
outcome = merged_mol.GetMol()
vprint(1, 'Merged editable mol, converted back to real mol, {}', Chem.MolToSmiles(outcome, True))
else:
new_outcome = outcome[0]
for j in range(1, len(outcome)):
new_outcome = AllChem.CombineMols(new_outcome, outcome[j])
outcome = new_outcome
vprint(2, 'Converted all outcomes to single molecules')
###############################################################################
###############################################################################
# Figure out which atoms were matched in the templates
# atoms_rt and atoms_p will be outcome-specific.
atoms_pt = {a.GetIsotope(): atoms_pt_map[a.GetIntProp('old_mapno')] \
for a in outcome.GetAtoms() if a.HasProp('old_mapno')}
atoms_p = {a.GetIsotope(): a for a in outcome.GetAtoms() if a.GetIsotope()}
# Set isotopes of product template
# note: this is okay to do within the loop, because ALL atoms must be matched
# in the templates, so the isotopes will get overwritten every time
# This makes it easier to check parity changes
#[a.SetIsotope(i) for (i, a) in atoms_pt.iteritems()]
[a.SetIsotope(i) for (i, a) in atoms_pt.items()]
###############################################################################
###############################################################################
# Check for missing bonds. These are bonds that are present in the reactants,
# not specified in the reactant template, and not in the product. Accidental
# fragmentation can occur for intramolecular ring openings
missing_bonds = []
for (i, j, b) in reactants.bonds_by_isotope:
if i in atoms_p and j in atoms_p:
# atoms from reactant bond show up in product
if not outcome.GetBondBetweenAtoms(atoms_p[i].GetIdx(), atoms_p[j].GetIdx()):
#...but there is not a bond in the product between those atoms
if i not in atoms_rt or j not in atoms_rt or not template_r.GetBondBetweenAtoms(atoms_rt[i].GetIdx(), atoms_rt[j].GetIdx()):
# the reactant template did not specify a bond between those atoms (e.g., intentionally destroy)
missing_bonds.append((i, j, b))
if missing_bonds:
vprint(1, 'Product is missing non-reacted bonds that were present in reactants!')
outcome = Chem.RWMol(outcome)
rwmol_iso_to_id = {a.GetIsotope(): a.GetIdx() for a in outcome.GetAtoms() if a.GetIsotope()}
for (i, j, b) in missing_bonds:
outcome.AddBond(rwmol_iso_to_id[i], rwmol_iso_to_id[j])
new_b = outcome.GetBondBetweenAtoms(rwmol_iso_to_id[i], rwmol_iso_to_id[j])
new_b.SetBondType(b.GetBondType())
new_b.SetBondDir(b.GetBondDir())
new_b.SetIsAromatic(b.GetIsAromatic())
outcome = outcome.GetMol()
else:
vprint(3, 'No missing bonds')
###############################################################################
# Now that we've fixed any bonds, connectivity is set. This is a good time
# to udpate the property cache, since all that is left is fixing atom/bond
# stereochemistry.
try:
outcome.UpdatePropertyCache()
except ValueError as e:
vprint(1, '{}, {}'.format(Chem.MolToSmiles(outcome, True), e))
continue
###############################################################################
# Correct tetra chirality in the outcome
for a in outcome.GetAtoms():
# Participants in reaction core (from reactants) will have old_mapno
# Spectators present in reactants will have react_atom_idx
# ...so new atoms will have neither!
if not a.HasProp('old_mapno'):
# Not part of the reactants template
if not a.HasProp('react_atom_idx'):
# Atoms only appear in product template - their chirality
# should be properly instantiated by RDKit...hopefully...
vprint(4, 'Atom {} created by product template, should have right chirality', a.GetIsotope())
else:
vprint(4, 'Atom {} outside of template, copy chirality from reactants', a.GetIsotope())
copy_chirality(atoms_r[a.GetIsotope()], a)
else:
# Part of reactants and reaction core
if template_atom_could_have_been_tetra(atoms_rt[a.GetIsotope()]):
vprint(3, 'Atom {} was in rct template (could have been tetra)', a.GetIsotope())
if template_atom_could_have_been_tetra(atoms_pt[a.GetIsotope()]):
vprint(3, 'Atom {} in product template could have been tetra, too', a.GetIsotope())
# Was the product template specified?
if atoms_pt[a.GetIsotope()].GetChiralTag() == ChiralType.CHI_UNSPECIFIED:
# No, leave unspecified in product
vprint(3, '...but it is not specified in product, so destroy chirality')
a.SetChiralTag(ChiralType.CHI_UNSPECIFIED)
else:
# Yes
vprint(3, '...and product is specified')
# Was the reactant template specified?
if atoms_rt[a.GetIsotope()].GetChiralTag() == ChiralType.CHI_UNSPECIFIED:
# No, so the reaction introduced chirality
vprint(3, '...but reactant template was not, so copy from product template')
copy_chirality(atoms_pt[a.GetIsotope()], a)
else:
# Yes, so we need to check if chirality should be preserved or inverted
vprint(3, '...and reactant template was, too! copy from reactants')
copy_chirality(atoms_r[a.GetIsotope()], a)
if not atom_chirality_matches(atoms_pt[a.GetIsotope()], atoms_rt[a.GetIsotope()]):
vprint(3, 'but! reactant template and product template have opposite stereochem, so invert')
a.InvertChirality()
else:
# Reactant template chiral, product template not - the
# reaction is supposed to destroy chirality, so leave
# unspecified
vprint(3, 'If reactant template could have been ' +
'chiral, but the product template could not, then we dont need ' +
'to worry about specifying product atom chirality')
else:
vprint(3, 'Atom {} could not have been chiral in reactant template', a.GetIsotope())
if not template_atom_could_have_been_tetra(atoms_pt[a.GetIsotope()]):
vprint(3, 'Atom {} also could not have been chiral in product template', a.GetIsotope())
vprint(3, '...so, copy chirality from reactant instead')
copy_chirality(atoms_r[a.GetIsotope()], a)
else:
vprint(3, 'Atom could/does have product template chirality!', a.GetIsotope())
vprint(3, '...so, copy chirality from product template')
copy_chirality(atoms_pt[a.GetIsotope()], a)
vprint(3, 'New chiral tag {}', a.GetChiralTag())
vprint(2, 'After attempting to re-introduce chirality, outcome = {}',
Chem.MolToSmiles(outcome, True))
###############################################################################
###############################################################################
# Correct bond directionality in the outcome
# TODO
# Clear isotope
if not keep_isotopes:
[a.SetIsotope(0) for a in outcome.GetAtoms()]
# Canonicalize
smiles = canonicalize_outcome_smiles(outcome)
if smiles is not None:
final_outcomes.add(smiles)
###############################################################################
# One last fix for consolidating multiple stereospecified products...
if combine_enantiomers:
final_outcomes = combine_enantiomers_into_racemic(final_outcomes)
###############################################################################
return list(final_outcomes)
def rdchiralRun(rxn, reactants, keep_isotopes=False, combine_enantiomers=True):
'''
rxn = rdchiralReaction (rdkit reaction + auxilliary information)
reactants = rdchiralReactants (rdkit mol + auxilliary information)
note: there is a fair amount of initialization (assigning stereochem), most
importantly assigning isotope numbers to the reactant atoms. It is
HIGHLY recommended to use the custom classes for initialization.
'''
final_outcomes = set()
# We need to keep track of what map numbers
# (i.e., isotopes) correspond to which atoms
# note: all reactant atoms must be mapped, so this is safe
atoms_r = reactants.atoms_r
# Copy reaction template so we can play around with isotopes
template_r, template_p = rxn.template_r, rxn.template_p
# Get molAtomMapNum->atom dictionary for tempalte reactants and products
atoms_rt_map = rxn.atoms_rt_map
atoms_pt_map = rxn.atoms_pt_map
###############################################################################
# Run naive RDKit on ACHIRAL version of molecules
outcomes = rxn.rxn.RunReactants((reactants.reactants_achiral, ))
vprint(2, 'Using naive RunReactants, {} outcomes', len(outcomes))
if not outcomes:
return []
###############################################################################
for outcome in outcomes:
###############################################################################
# Look for new atoms in products that were not in
# reactants (e.g., LGs for a retro reaction)
vprint(2, 'Processing {}',
str([Chem.MolToSmiles(x, True) for x in outcome]))
unmapped = 900
for m in outcome:
for a in m.GetAtoms():
# Assign "map" number via isotope
if not a.GetIsotope():
a.SetIsotope(unmapped)
unmapped += 1
vprint(2, 'Added {} map numbers to product', unmapped - 900)
###############################################################################
###############################################################################
# Check to see if reactants should not have been matched (based on chirality)
# Define isotope -> reactant template atom map
atoms_rt = {a.GetIsotope(): atoms_rt_map[a.GetIntProp('old_mapno')] \
for m in outcome for a in m.GetAtoms() if a.HasProp('old_mapno')}
# Set isotopes of reactant template
# note: this is okay to do within the loop, because ALL atoms must be matched
# in the templates, so the isotopes will get overwritten every time
[a.SetIsotope(i) for (i, a) in atoms_rt.items()]
# Make sure each atom matches
if not all(
atom_chirality_matches(atoms_rt[i], atoms_r[i])
for i in atoms_rt):
vprint(2, 'Chirality violated! Should not have gotten this match')
continue
vprint(2,
'Chirality matches! Just checked with atom_chirality_matches')
# Check bond chirality
#TODO: add bond chirality considerations to exclude improper matches
###############################################################################
###############################################################################
# Convert product(s) to single product so that all
# reactions can be treated as pseudo-intramolecular
# But! check for ring openings mistakenly split into multiple
# This can be diagnosed by duplicate map numbers (i.e., SMILES)
isotopes = [
a.GetIsotope() for m in outcome for a in m.GetAtoms()
if a.GetIsotope()
]
if len(isotopes) != len(set(isotopes)): # duplicate?
vprint(1, 'Found duplicate isotopes in product - need to stitch')
# need to do a fancy merge
merged_mol = Chem.RWMol(outcome[0])
merged_iso_to_id = {
a.GetIsotope(): a.GetIdx()
for a in outcome[0].GetAtoms() if a.GetIsotope()
}
for j in range(1, len(outcome)):
new_mol = outcome[j]
for a in new_mol.GetAtoms():
if a.GetIsotope() not in merged_iso_to_id:
merged_iso_to_id[a.GetIsotope()] = merged_mol.AddAtom(
a)
for b in new_mol.GetBonds():
bi = b.GetBeginAtom().GetIsotope()
bj = b.GetEndAtom().GetIsotope()
vprint(
10,
'stitching bond between {} and {} in stich has chirality {}, {}'
.format(bi, bj, b.GetStereo(), b.GetBondDir()))
if not merged_mol.GetBondBetweenAtoms(
merged_iso_to_id[bi], merged_iso_to_id[bj]):
merged_mol.AddBond(merged_iso_to_id[bi],
merged_iso_to_id[bj],
b.GetBondType())
merged_mol.GetBondBetweenAtoms(
merged_iso_to_id[bi],
merged_iso_to_id[bj]).SetStereo(b.GetStereo())
merged_mol.GetBondBetweenAtoms(
merged_iso_to_id[bi],
merged_iso_to_id[bj]).SetBondDir(b.GetBondDir())
outcome = merged_mol.GetMol()
vprint(1, 'Merged editable mol, converted back to real mol, {}',
Chem.MolToSmiles(outcome, True))
else:
new_outcome = outcome[0]
for j in range(1, len(outcome)):
new_outcome = AllChem.CombineMols(new_outcome, outcome[j])
outcome = new_outcome
vprint(2, 'Converted all outcomes to single molecules')
###############################################################################
###############################################################################
# Figure out which atoms were matched in the templates
# atoms_rt and atoms_p will be outcome-specific.
atoms_pt = {a.GetIsotope(): atoms_pt_map[a.GetIntProp('old_mapno')] \
for a in outcome.GetAtoms() if a.HasProp('old_mapno')}
atoms_p = {
a.GetIsotope(): a
for a in outcome.GetAtoms() if a.GetIsotope()
}
# Set isotopes of product template
# note: this is okay to do within the loop, because ALL atoms must be matched
# in the templates, so the isotopes will get overwritten every time
# This makes it easier to check parity changes
#[a.SetIsotope(i) for (i, a) in atoms_pt.iteritems()]
[a.SetIsotope(i) for (i, a) in atoms_pt.items()]
###############################################################################
###############################################################################
# Check for missing bonds. These are bonds that are present in the reactants,
# not specified in the reactant template, and not in the product. Accidental
# fragmentation can occur for intramolecular ring openings
missing_bonds = []
for (i, j, b) in reactants.bonds_by_isotope:
if i in atoms_p and j in atoms_p:
# atoms from reactant bond show up in product
if not outcome.GetBondBetweenAtoms(atoms_p[i].GetIdx(),
atoms_p[j].GetIdx()):
#...but there is not a bond in the product between those atoms
if i not in atoms_rt or j not in atoms_rt or not template_r.GetBondBetweenAtoms(
atoms_rt[i].GetIdx(), atoms_rt[j].GetIdx()):
# the reactant template did not specify a bond between those atoms (e.g., intentionally destroy)
missing_bonds.append((i, j, b))
if missing_bonds:
vprint(
1,
'Product is missing non-reacted bonds that were present in reactants!'
)
outcome = Chem.RWMol(outcome)
rwmol_iso_to_id = {
a.GetIsotope(): a.GetIdx()
for a in outcome.GetAtoms() if a.GetIsotope()
}
for (i, j, b) in missing_bonds:
outcome.AddBond(rwmol_iso_to_id[i], rwmol_iso_to_id[j])
new_b = outcome.GetBondBetweenAtoms(rwmol_iso_to_id[i],
rwmol_iso_to_id[j])
new_b.SetBondType(b.GetBondType())
new_b.SetBondDir(b.GetBondDir())
new_b.SetIsAromatic(b.GetIsAromatic())
outcome = outcome.GetMol()
else:
vprint(3, 'No missing bonds')
###############################################################################
# Now that we've fixed any bonds, connectivity is set. This is a good time
# to udpate the property cache, since all that is left is fixing atom/bond
# stereochemistry.
try:
outcome.UpdatePropertyCache()
except ValueError as e:
vprint(1, '{}, {}'.format(Chem.MolToSmiles(outcome, True), e))
continue
###############################################################################
# Correct tetra chirality in the outcome
for a in outcome.GetAtoms():
# Participants in reaction core (from reactants) will have old_mapno
# Spectators present in reactants will have react_atom_idx
# ...so new atoms will have neither!
if not a.HasProp('old_mapno'):
# Not part of the reactants template
if not a.HasProp('react_atom_idx'):
# Atoms only appear in product template - their chirality
# should be properly instantiated by RDKit...hopefully...
vprint(
4,
'Atom {} created by product template, should have right chirality',
a.GetIsotope())
else:
vprint(
4,
'Atom {} outside of template, copy chirality from reactants',
a.GetIsotope())
copy_chirality(atoms_r[a.GetIsotope()], a)
else:
# Part of reactants and reaction core
if template_atom_could_have_been_tetra(
atoms_rt[a.GetIsotope()]):
vprint(
3,
'Atom {} was in rct template (could have been tetra)',
a.GetIsotope())
if template_atom_could_have_been_tetra(
atoms_pt[a.GetIsotope()]):
vprint(
3,
'Atom {} in product template could have been tetra, too',
a.GetIsotope())
# Was the product template specified?
if atoms_pt[a.GetIsotope()].GetChiralTag(
) == ChiralType.CHI_UNSPECIFIED:
# No, leave unspecified in product
vprint(
3,
'...but it is not specified in product, so destroy chirality'
)
a.SetChiralTag(ChiralType.CHI_UNSPECIFIED)
else:
# Yes
vprint(3, '...and product is specified')
# Was the reactant template specified?
if atoms_rt[a.GetIsotope()].GetChiralTag(
) == ChiralType.CHI_UNSPECIFIED:
# No, so the reaction introduced chirality
vprint(
3,
'...but reactant template was not, so copy from product template'
)
copy_chirality(atoms_pt[a.GetIsotope()], a)
else:
# Yes, so we need to check if chirality should be preserved or inverted
vprint(
3,
'...and reactant template was, too! copy from reactants'
)
copy_chirality(atoms_r[a.GetIsotope()], a)
if not atom_chirality_matches(
atoms_pt[a.GetIsotope()],
atoms_rt[a.GetIsotope()]):
vprint(
3,
'but! reactant template and product template have opposite stereochem, so invert'
)
a.InvertChirality()
else:
# Reactant template chiral, product template not - the
# reaction is supposed to destroy chirality, so leave
# unspecified
vprint(
3, 'If reactant template could have been ' +
'chiral, but the product template could not, then we dont need '
+
'to worry about specifying product atom chirality')
else:
vprint(
3,
'Atom {} could not have been chiral in reactant template',
a.GetIsotope())
if not template_atom_could_have_been_tetra(
atoms_pt[a.GetIsotope()]):
vprint(
3,
'Atom {} also could not have been chiral in product template',
a.GetIsotope())
vprint(3,
'...so, copy chirality from reactant instead')
copy_chirality(atoms_r[a.GetIsotope()], a)
else:
vprint(
3,
'Atom could/does have product template chirality!',
a.GetIsotope())
vprint(3,
'...so, copy chirality from product template')
copy_chirality(atoms_pt[a.GetIsotope()], a)
vprint(3, 'New chiral tag {}', a.GetChiralTag())
vprint(2, 'After attempting to re-introduce chirality, outcome = {}',
Chem.MolToSmiles(outcome, True))
###############################################################################
###############################################################################
# Correct bond directionality in the outcome
# TODO
# Clear isotope
if not keep_isotopes:
[a.SetIsotope(0) for a in outcome.GetAtoms()]
# Canonicalize
smiles = canonicalize_outcome_smiles(outcome)
if smiles is not None:
final_outcomes.add(smiles)
###############################################################################
# One last fix for consolidating multiple stereospecified products...
if combine_enantiomers:
final_outcomes = combine_enantiomers_into_racemic(final_outcomes)
###############################################################################
return list(final_outcomes)
