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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 <algorithm>
#include <DataStructs/BitOps.h>
#include <GraphMol/MolOps.h>
#include <GraphMol/SmilesParse/SmilesParse.h>
#include <GraphMol/SmilesParse/SmilesWrite.h>
#include <GraphMol/SynthonSpaceSearch/SynthonSpaceSearch_details.h>
#include <GraphMol/SynthonSpaceSearch/SynthonSpaceFingerprintSearcher.h>
#include <RDGeneral/ControlCHandler.h>
namespace RDKit::SynthonSpaceSearch {
SynthonSpaceFingerprintSearcher::SynthonSpaceFingerprintSearcher(
const ROMol &query, const FingerprintGenerator<std::uint64_t> &fpGen,
const SynthonSpaceSearchParams ¶ms, SynthonSpace &space)
: SynthonSpaceSearcher(query, params, space), d_fpGen(fpGen) {
if (getSpace().hasFingerprints() &&
d_fpGen.infoString() != getSpace().getSynthonFingerprintType()) {
throw std::runtime_error(
"The search fingerprints must match"
" those in the database. You are searching with " +
d_fpGen.infoString() + " vs " + getSpace().getSynthonFingerprintType() +
" in the database.");
}
d_queryFP = std::unique_ptr<ExplicitBitVect>(d_fpGen.getFingerprint(query));
}
namespace {
// Take the fragged mol fps and flag all those synthons that have a fragment as
// a similarity match.
std::vector<std::vector<size_t>> getHitSynthons(
const std::vector<ExplicitBitVect *> &fragFPs,
const double similarityCutoff, const SynthonSet &reaction,
const std::vector<unsigned int> &synthonOrder) {
std::vector<boost::dynamic_bitset<>> synthonsToUse;
std::vector<std::vector<size_t>> retSynthons;
std::vector<std::vector<std::pair<size_t, double>>> fragSims(
reaction.getSynthons().size());
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++) {
// There's a simple calculation for the maximum possible Tanimoto
// Coefficient that these 2 fingerprints can achieve.
const double maxSim =
fragFPs[i]->getNumOnBits() <
synthons[j].second->getFP()->getNumOnBits()
? static_cast<double>(fragFPs[i]->getNumOnBits()) /
synthons[j].second->getFP()->getNumOnBits()
: static_cast<double>(
synthons[j].second->getFP()->getNumOnBits()) /
fragFPs[i]->getNumOnBits();
if (maxSim < similarityCutoff) {
continue;
}
if (const auto sim =
TanimotoSimilarity(*fragFPs[i], *synthons[j].second->getFP());
sim >= similarityCutoff) {
synthonsToUse[synthonOrder[i]][j] = true;
fragSims[synthonOrder[i]].emplace_back(j, sim);
fragMatched = true;
}
}
if (!fragMatched) {
// No synthons matched this fragment, so the whole fragment set is a
// bust.
return retSynthons;
}
}
// Fill in any synthons where they all didn't match because there were
// fewer fragments than synthons.
details::expandBitSet(synthonsToUse);
details::bitSetsToVectors(synthonsToUse, retSynthons);
// Now order the synthons in descending order of their similarity to
// the corresponding fragFP.
for (size_t i = 0; i < fragFPs.size(); i++) {
if (fragSims[i].empty()) {
// This one will have been filled in by expandBitSet so we need to use
// all the synthons and a dummy similarity.
fragSims[i].resize(synthonsToUse[i].size());
for (size_t j = 0; j < fragSims[i].size(); j++) {
fragSims[i][j] = std::make_pair(j, 0.0);
}
} else {
std::sort(
fragSims[i].begin(), fragSims[i].end(),
[](const auto &a, const auto &b) { return a.second > b.second; });
}
retSynthons[i].clear();
std::transform(fragSims[i].begin(), fragSims[i].end(),
std::back_inserter(retSynthons[i]),
[](const auto &fs) { return fs.first; });
}
return retSynthons;
}
} // namespace
void SynthonSpaceFingerprintSearcher::extraSearchSetup(
std::vector<std::vector<std::unique_ptr<ROMol>>> &fragSets) {
if (!getSpace().hasFingerprints() ||
getSpace().getSynthonFingerprintType() != d_fpGen.infoString()) {
getSpace().buildSynthonFingerprints(d_fpGen);
}
if (ControlCHandler::getGotSignal()) {
return;
}
// Slightly convoluted way of doing it to prepare for multi-threading.
// Make a map of the unique SMILES strings for the fragments, keeping
// track of them in the vector.
bool cancelled = false;
auto fragSmiToFrag = details::mapFragsBySmiles(fragSets, cancelled);
if (cancelled) {
return;
}
// Now generate the fingerprints for the fragments. This is the
// time-consuming bit that will be threaded.
d_fragFPPool.resize(fragSmiToFrag.size());
unsigned int fragNum = 0;
for (auto &[fragSmi, frags] : fragSmiToFrag) {
if (ControlCHandler::getGotSignal()) {
return;
}
d_fragFPPool[fragNum++].reset(d_fpGen.getFingerprint(*frags.front()));
}
// Now use the pooled fps to populate the vectors for each fragSet.
fragNum = 0;
d_fragFPs.reserve(fragSmiToFrag.size());
for (auto &[fragSmi, frags] : fragSmiToFrag) {
for (auto &frag : frags) {
d_fragFPs.emplace_back(frag, d_fragFPPool[fragNum].get());
}
++fragNum;
}
std::sort(d_fragFPs.begin(), d_fragFPs.end(),
[](const auto &p1, const auto &p2) -> bool {
return p1.first > p2.first;
});
}
std::vector<std::unique_ptr<SynthonSpaceHitSet>>
SynthonSpaceFingerprintSearcher::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;
}
std::vector<ExplicitBitVect *> fragFPs;
fragFPs.reserve(fragSet.size());
for (auto &frag : fragSet) {
std::pair<void *, ExplicitBitVect *> tmp{frag.get(), nullptr};
const auto it =
std::lower_bound(d_fragFPs.begin(), d_fragFPs.end(), tmp,
[](const auto &p1, const auto &p2) -> bool {
return p1.first > p2.first;
});
fragFPs.push_back(it->second);
}
const auto connPatterns = details::getConnectorPatterns(fragSet);
const 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.
const 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;
}
// It appears that for fingerprints, the isotope numbers are
// ignored so there's no need to worry about the connector numbers
// in the fingerprints.
auto theseSynthons = getHitSynthons(
fragFPs,
getParams().similarityCutoff - getParams().fragSimilarityAdjuster,
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 SynthonSpaceFingerprintSearcher::quickVerify(
const SynthonSpaceHitSet *hitset,
const std::vector<size_t> &synthNums) const {
// The hitsets produced by the fingerprint searcher are SynthonSpaceFPHitSets,
// which have the synthon fps as well.
const auto hs = dynamic_cast<const SynthonSpaceFPHitSet *>(hitset);
// Make an approximate fingerprint by combining the FPs for
// these synthons, adding in the addFP and taking out the
// subtractFP.
ExplicitBitVect fullFP(*hs->synthonFPs[0][synthNums[0]]);
for (unsigned int i = 1; i < synthNums.size(); ++i) {
fullFP |= *hs->synthonFPs[i][synthNums[i]];
}
fullFP |= *hs->addFP;
// The subtract FP has already had its bits flipped, so just do a
// straight AND.
fullFP &= *hs->subtractFP;
return TanimotoSimilarity(fullFP, *d_queryFP) >=
getParams().similarityCutoff - getParams().approxSimilarityAdjuster;
}
bool SynthonSpaceFingerprintSearcher::verifyHit(const ROMol &hit) const {
const std::unique_ptr<ExplicitBitVect> fp(d_fpGen.getFingerprint(hit));
if (const auto sim = TanimotoSimilarity(*fp, *d_queryFP);
sim >= getParams().similarityCutoff) {
hit.setProp<double>("Similarity", sim);
return true;
}
return false;
}
} // namespace RDKit::SynthonSpaceSearch
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