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//
// Copyright (C) David Cosgrove 2024.
//
// @@ All Rights Reserved @@
// This file is part of the RDKit.
// The contents are covered by the terms of the BSD license
// which is included in the file license.txt, found at the root
// of the RDKit source tree.
//
#include <DataStructs/BitOps.h>
#include <GraphMol/MolOps.h>
#include <GraphMol/SmilesParse/SmilesWrite.h>
#include <GraphMol/RascalMCES/RascalMCES.h>
#include <GraphMol/SynthonSpaceSearch/SynthonSpaceSearch_details.h>
#include <GraphMol/SynthonSpaceSearch/SynthonSpaceRascalSearcher.h>
namespace RDKit::SynthonSpaceSearch {
SynthonSpaceRascalSearcher::SynthonSpaceRascalSearcher(
const ROMol &query, const RascalMCES::RascalOptions &rascalOptions,
const SynthonSpaceSearchParams ¶ms, SynthonSpace &space)
: SynthonSpaceSearcher(query, params, space),
d_rascalOptions(rascalOptions),
d_rascalFragOptions(rascalOptions) {
d_rascalFragOptions.similarityThreshold -= params.fragSimilarityAdjuster;
}
namespace {
std::vector<std::vector<size_t>> getHitSynthons(
const std::vector<std::unique_ptr<ROMol>> &fragSet,
const RascalMCES::RascalOptions &rascalOptions, const SynthonSet &reaction,
const std::vector<unsigned int> &synthonOrder) {
std::vector<boost::dynamic_bitset<>> synthonsToUse;
std::vector<std::vector<size_t>> retSynthons;
synthonsToUse.reserve(reaction.getSynthons().size());
for (const auto &synthonSet : reaction.getSynthons()) {
synthonsToUse.emplace_back(synthonSet.size());
}
for (size_t i = 0; i < synthonOrder.size(); i++) {
const auto &synthons = reaction.getSynthons()[synthonOrder[i]];
bool fragMatched = false;
for (size_t j = 0; j < synthons.size(); j++) {
const auto rascalResults = RascalMCES::rascalMCES(
*fragSet[i], *synthons[j].second->getSearchMol(), rascalOptions);
if (!rascalResults.empty()) {
synthonsToUse[synthonOrder[i]][j] = true;
fragMatched = true;
}
}
if (!fragMatched) {
return retSynthons;
}
}
// Fill in any synthons where they all didn't match.
details::expandBitSet(synthonsToUse);
details::bitSetsToVectors(synthonsToUse, retSynthons);
// Now sort the selected synthons into ascending order of number of
// atoms, since smaller molecules are likely to be of more interest.
for (size_t i = 0; i < retSynthons.size(); ++i) {
const auto &synthonsi = reaction.getSynthons()[i];
std::sort(retSynthons[i].begin(), retSynthons[i].end(),
[&](const size_t a, const size_t b) {
return synthonsi[a].second->getOrigMol()->getNumAtoms() <
synthonsi[b].second->getOrigMol()->getNumAtoms();
});
}
return retSynthons;
}
} // namespace
void SynthonSpaceRascalSearcher::extraSearchSetup(
std::vector<std::vector<std::unique_ptr<ROMol>>> &fragSets) {
for (const auto &fragSet : fragSets) {
for (const auto &frag : fragSet) {
unsigned int otf;
sanitizeMol(*static_cast<RWMol *>(frag.get()), otf,
MolOps::SANITIZE_SYMMRINGS);
}
}
}
std::vector<std::unique_ptr<SynthonSpaceHitSet>>
SynthonSpaceRascalSearcher::searchFragSet(
const std::vector<std::unique_ptr<ROMol>> &fragSet,
const SynthonSet &reaction) const {
std::vector<std::unique_ptr<SynthonSpaceHitSet>> results;
// It can't be a hit if the number of fragments is more than the number
// of synthon sets because some of the molecule won't be matched in any
// of the potential products. It can be less, in which case the unused
// synthon set will be used completely, possibly resulting in a large
// number of hits.
if (fragSet.size() > reaction.getSynthons().size()) {
return results;
}
const auto connPatterns = details::getConnectorPatterns(fragSet);
boost::dynamic_bitset<> conns(MAX_CONNECTOR_NUM + 1);
for (auto &connPattern : connPatterns) {
conns |= connPattern;
}
auto synthConnPatts = reaction.getSynthonConnectorPatterns();
// Get all the possible permutations of connector numbers compatible with
// the number of synthon sets in this reaction. So if the
// fragmented molecule is C[1*].N[2*] and there are 3 synthon sets
// we also try C[2*].N[1*], C[2*].N[3*] and C[3*].N[2*] because
// that might be how they're labelled in the reaction database.
const auto connCombConnPatterns =
details::getConnectorPermutations(connPatterns, reaction.getConnectors());
// Need to try all combinations of synthon orders.
auto synthonOrders =
details::permMFromN(fragSet.size(), reaction.getSynthons().size());
for (const auto &synthonOrder : synthonOrders) {
for (auto &connCombPatt : connCombConnPatterns) {
// Make sure that for this connector combination, the synthons in this
// order have something similar. All query fragment connectors must
// match something in the corresponding synthon. The synthon can
// have unused connectors.
bool skip = false;
for (size_t i = 0; i < connCombPatt.size(); ++i) {
if ((connCombPatt[i] & synthConnPatts[synthonOrder[i]]).count() <
connCombPatt[i].count()) {
skip = true;
break;
}
}
if (skip) {
continue;
}
// Rascal ignores isotope numbers, which makes things easier.
auto theseSynthons =
getHitSynthons(fragSet, d_rascalFragOptions, reaction, synthonOrder);
if (!theseSynthons.empty()) {
std::unique_ptr<SynthonSpaceHitSet> hs(
new SynthonSpaceFPHitSet(reaction, theseSynthons, fragSet));
if (hs->numHits) {
results.push_back(std::move(hs));
}
}
}
}
return results;
}
bool SynthonSpaceRascalSearcher::quickVerify(
const SynthonSpaceHitSet *hitset,
const std::vector<size_t> &synthNums) const {
// If the query is an exact substructure of the product, then that's an upper
// bound on the Johnson similarity. Check that that is not below the
// threshold.
int qbit = getQuery().getNumAtoms() + getQuery().getNumBonds();
int numAtoms = 0, numBonds = 0;
for (size_t i = 0; i < synthNums.size(); i++) {
const auto &smol = hitset->synthonsToUse[i][synthNums[i]].second;
// Adjust for connector points that aren't in the final product.
numAtoms += smol->getNumAtoms() -
hitset->d_reaction->getSynthonConnectorPatterns()[i].count();
numBonds += smol->getNumBonds() -
hitset->d_reaction->getSynthonConnectorPatterns()[i].count();
}
// The Johnson similarity is
// (commonNatoms + commonNbonds)**2 /
// ((Natoms1 + Nbonds1) * (Natoms2 + Natoms2))
// and in this case the common atoms are the whole query, so the square
// cancels out.
double bestSim =
static_cast<double>(qbit) / static_cast<double>(numAtoms + numBonds);
return bestSim >= d_rascalOptions.similarityThreshold;
}
bool SynthonSpaceRascalSearcher::verifyHit(const ROMol &hit) const {
auto res = RascalMCES::rascalMCES(hit, getQuery(), d_rascalOptions);
// Rascal reports all matches that proceed to full MCES elucidation,
// even if the final similarity value ends up below the threshold.
// We only want those over the threshold.
if (!res.empty() &&
res.front().getSimilarity() >= d_rascalOptions.similarityThreshold) {
hit.setProp<double>("Similarity", res.front().getSimilarity());
return true;
}
return false;
}
} // namespace RDKit::SynthonSpaceSearch
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