[Rdkit-discuss] Exhaustive Library Enumeration

[Andy J. <and...@gm...>]

Hi RDKitters,

I have a question and an observation on the topic of library enumeration.

First, the question: is there a call within RDKit to trigger the exhaustive
reaction of reagents? For example, if I have two reagents - a primary amine
and an akyl chloride - can I tell RDKit to enumerate the reaction as though
there were an excess of each reagent? In my case here the reaction would
continue until the alkylation can no longer occur because there are no more
valences available on the amine and I would either be tri-alkylated for a
neutral product or quat-alkylated for a positively charged product
e.g. CCN + RCl -> CCN(R)(R)R or CC[N+](R)(R)(R)R

This brings me to my observation. When I try to attempt exactly this by
repeatedly exposing the product to the reagent again I am able to drive it
to exhaustion *in some cases*.

For example, in the example above where RCl is benzyl chloride and my
smirks is:
[#7:1].[#6:2][Cl:3]>>[#6:2][#7:1].[Cl:3]'
I do drive the final product to be exclusively the tri-akylated amine.
Success.

However, when I attempt the same thing with an amine with more than one
reactive nitrogen (e.g. NCCCCN) I don't get a single product with 6
alkylations, I get two unique product each with three alkylations. One
product has two alkylations on the first nitrogen and one on the second,
the other product has three alkylations on the first nitrogen and none on
the second. Attempting to drive the reaction once again leads to a
'reaction called with None reactants' ValueError. My dreadful code is below
and the output is
Reaction 1: ['NCCCCNCc1ccccc1']
Reaction 2: ['NCCCCN(Cc1ccccc1)Cc1ccccc1', 'c1ccc(CNCCCCNCc2ccccc2)cc1']
Reaction 3: ['c1ccc(CNCCCCN(Cc2ccccc2)Cc2ccccc2)cc1',
'NCCCCN(Cc1ccccc1)(Cc1ccccc1)Cc1ccccc1']
Reaction 4: ValueError

Any pointers would be great, as would any pre-existing library enumeration
code. The examples I've found shipped with RDKit don't appear to allow me
to name the products using a combination of the reagent names (useful for
tracking library content).

Best,
Andy

#### Code snippet ####

amine = Chem.MolFromSmiles('NCCCCN')
acyl = Chem.MolFromSmiles('c1ccccc1CCl')
rxn = AllChem.ReactionFromSmarts('[#7:1].[#6:2][Cl:3]>>[#6:2][#7:1].[Cl:3]')

# First reaction
reactantListMols = [amine,acyl]
prods =
AllChem.EnumerateLibraryFromReaction(rxn,[reactantListMols,reactantListMols])
prods = list(prods)
smis = list(set([Chem.MolToSmiles(x[0],isomericSmiles=True) for x in
prods]))
print smis
# ['NCCCCNCc1ccccc1']

# Now repeat until doom
for i in range(0,10):
    oldproducts = [Chem.MolFromSmiles(x) for x in smis]
    reactantListMols = oldproducts + [acyl]
    prods =
AllChem.EnumerateLibraryFromReaction(rxn,[reactantListMols,reactantListMols])
    prods = list(prods)
    smis = list(set([Chem.MolToSmiles(x[0],isomericSmiles=True) for x in
prods]))
    print smis

#### End Code ####