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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 <chrono>
#include <filesystem>
#include <fstream>
#include <GraphMol/Descriptors/MolDescriptors.h>
#include <GraphMol/FileParsers/MolSupplier.h>
#include <GraphMol/Fingerprints/MorganGenerator.h>
#include <GraphMol/Fingerprints/RDKitFPGenerator.h>
#include <GraphMol/SubstructLibrary/SubstructLibrary.h>
#include <GraphMol/SynthonSpaceSearch/SynthonSpace.h>
#include <GraphMol/SynthonSpaceSearch/SearchResults.h>
#include <GraphMol/SynthonSpaceSearch/SynthonSpaceSearch_details.h>
#include <GraphMol/SmilesParse/SmilesParse.h>
#include <GraphMol/SmilesParse/SmilesWrite.h>
#include <catch2/catch_all.hpp>
using namespace RDKit;
using namespace RDKit::SynthonSpaceSearch;
using namespace RDKit::SynthonSpaceSearch::details;
const char *rdbase = getenv("RDBASE");
std::map<std::string, std::unique_ptr<ExplicitBitVect>> getFingerprints(
const std::string &molFilename,
std::map<std::string, std::unique_ptr<RWMol>> &mols,
const std::unique_ptr<FingerprintGenerator<std::uint64_t>> &fpGen) {
v2::FileParsers::SmilesMolSupplierParams fileparams;
fileparams.titleLine = false;
v2::FileParsers::SmilesMolSupplier suppl(molFilename, fileparams);
std::map<std::string, std::unique_ptr<ExplicitBitVect>> fps;
while (!suppl.atEnd()) {
auto mol = suppl.next();
auto fp = fpGen->getFingerprint(*mol);
fps.insert(std::make_pair(
mol->getProp<std::string>(common_properties::_Name), fp));
auto molName = mol->getProp<std::string>(common_properties::_Name);
mols.insert(std::make_pair(molName, mol.release()));
}
return fps;
}
std::set<std::string> bruteForceSearch(
std::map<std::string, std::unique_ptr<ExplicitBitVect>> &fps,
const ROMol &queryMol, const double simCutoff) {
std::unique_ptr<FingerprintGenerator<std::uint64_t>> fpGen;
fpGen.reset(MorganFingerprint::getMorganGenerator<std::uint64_t>(2));
const auto queryFP =
std::unique_ptr<ExplicitBitVect>(fpGen->getFingerprint(queryMol));
std::set<std::string> fullSmi;
std::set<std::string> names;
for (auto &it : fps) {
if (auto sim = TanimotoSimilarity(*it.second, *queryFP); sim >= simCutoff) {
names.insert(it.first);
}
}
return names;
}
TEST_CASE("FP Small tests") {
REQUIRE(rdbase);
std::string fName(rdbase);
std::string fullRoot(fName + "/Code/GraphMol/SynthonSpaceSearch/data/");
std::vector<std::string> libNames{
fullRoot + "amide_space.txt",
fullRoot + "triazole_space.txt",
fullRoot + "urea_space.txt",
};
std::vector<std::string> enumLibNames{
fullRoot + "amide_space_enum.smi",
fullRoot + "triazole_space_enum.smi",
fullRoot + "urea_space_enum.smi",
};
std::vector<std::string> querySmis{
"c1ccccc1C(=O)N1CCCC1",
"CC1CCN(c2nnc(CO)n2C2CCCC2)C1",
"C[C@@H]1CC(NC(=O)NC2COC2)CN(C(=O)c2nccnc2F)C1",
};
std::vector<size_t> expNumHits{2, 3, 4};
for (size_t i = 0; i < libNames.size(); i++) {
SynthonSpace synthonspace;
bool cancelled = false;
synthonspace.readTextFile(libNames[i], cancelled);
SynthonSpaceSearchParams params;
params.randomSeed = 1;
params.approxSimilarityAdjuster = 0.2;
auto queryMol = v2::SmilesParse::MolFromSmiles(querySmis[i]);
std::unique_ptr<FingerprintGenerator<std::uint64_t>> fpGen(
MorganFingerprint::getMorganGenerator<std::uint64_t>(2));
auto results = synthonspace.fingerprintSearch(*queryMol, *fpGen, params);
CHECK(results.getHitMolecules().size() == expNumHits[i]);
std::set<std::string> resSmis;
for (const auto &r : results.getHitMolecules()) {
resSmis.insert(MolToSmiles(*r));
}
// Do the enumerated library, just to check
std::map<std::string, std::unique_ptr<RWMol>> mols;
auto fps = getFingerprints(enumLibNames[i], mols, fpGen);
auto names = bruteForceSearch(fps, *queryMol, params.similarityCutoff);
std::set<std::string> fullSmis;
for (const auto &r : names) {
fullSmis.insert(MolToSmiles(*mols[r]));
}
if (i != 1) {
CHECK(resSmis == fullSmis);
} else {
// In the triazole library, one of the hits found by the brute force
// method (triazole-1_1-1_2-2_3-1) is missed by the SynthonSpaceSearch
// because it requires that the fragment [1*]n([3*])C1CCCC1 is similar
// to synthon c1ccccc1-n([3*])[1*] which it isn't. Instead, make sure
// all the ones that are found are in the brute force results.
for (const auto &rs : resSmis) {
CHECK(fullSmis.find(rs) != fullSmis.end());
}
}
}
}
TEST_CASE("FP Binary File") {
REQUIRE(rdbase);
std::string fName(rdbase);
SynthonSpace synthonspace;
std::string libName =
fName + "/Code/GraphMol/SynthonSpaceSearch/data/idorsia_toy_space_a.spc";
std::unique_ptr<FingerprintGenerator<std::uint64_t>> fpGen(
RDKitFP::getRDKitFPGenerator<std::uint64_t>());
SearchResults results;
auto queryMol = "O=C(Nc1c(CNC=O)cc[s]1)c1nccnc1"_smiles;
SynthonSpaceSearchParams params;
for (auto numThreads : std::vector<int>{1, 2, -1}) {
synthonspace.readDBFile(libName, numThreads);
params.numThreads = numThreads;
CHECK_NOTHROW(
results = synthonspace.fingerprintSearch(*queryMol, *fpGen, params));
CHECK(results.getHitMolecules().size() == 4);
CHECK(results.getMaxNumResults() == 420);
}
// Make sure it rejects the wrong sort of fingerprint.
synthonspace.readDBFile(libName);
fpGen.reset(MorganFingerprint::getMorganGenerator<std::uint64_t>(2));
CHECK_THROWS(results = synthonspace.fingerprintSearch(*queryMol, *fpGen));
}
TEST_CASE("Missing exact match") {
REQUIRE(rdbase);
std::string fName(rdbase);
SynthonSpace synthonspace;
std::string libName =
fName + "/Code/GraphMol/SynthonSpaceSearch/data/missing_hit.txt";
std::unique_ptr<FingerprintGenerator<std::uint64_t>> fpGen(
RDKitFP::getRDKitFPGenerator<std::uint64_t>());
SearchResults results;
auto queryMol =
"N#Cc1ccc(C(=O)Cn2cc(-c3cn[nH]c3-c3nc4ccccc4[nH]3)nn2)s1"_smiles;
bool cancelled = false;
synthonspace.readTextFile(libName, cancelled);
synthonspace.buildSynthonFingerprints(*fpGen);
CHECK_NOTHROW(results = synthonspace.fingerprintSearch(*queryMol, *fpGen));
CHECK(results.getHitMolecules().size() == 1);
CHECK(results.getHitMolecules()[0]->getProp<double>("Similarity") == 1.0);
}
TEST_CASE("Hit Filters") {
REQUIRE(rdbase);
std::string fName(rdbase);
SynthonSpace synthonspace;
std::string libName =
fName + "/Code/GraphMol/SynthonSpaceSearch/data/idorsia_toy_space_a.spc";
std::unique_ptr<FingerprintGenerator<std::uint64_t>> fpGen(
RDKitFP::getRDKitFPGenerator<std::uint64_t>());
SearchResults results;
auto queryMol = "CCNC(=O)Cc1cncc(CCOC2c3ccccc3CC2)c1"_smiles;
SynthonSpaceSearchParams params;
params.similarityCutoff = 0.45;
synthonspace.readDBFile(libName);
results = synthonspace.fingerprintSearch(*queryMol, *fpGen, params);
CHECK(results.getHitMolecules().size() == 18);
{
SynthonSpaceSearchParams params;
params.minHitHeavyAtoms = 28;
params.similarityCutoff = 0.45;
results = synthonspace.fingerprintSearch(*queryMol, *fpGen, params);
CHECK(results.getHitMolecules().size() == 13);
params.maxHitHeavyAtoms = 29;
results = synthonspace.fingerprintSearch(*queryMol, *fpGen, params);
CHECK(results.getHitMolecules().size() == 12);
for (const auto &r : results.getHitMolecules()) {
auto numHeavies = Descriptors::calcNumHeavyAtoms(*r);
CHECK((numHeavies == 28 || numHeavies == 29));
}
}
{
SynthonSpaceSearchParams params;
params.similarityCutoff = 0.45;
params.minHitMolWt = 375.0;
results = synthonspace.fingerprintSearch(*queryMol, *fpGen, params);
CHECK(results.getHitMolecules().size() == 13);
params.maxHitMolWt = 390.0;
results = synthonspace.fingerprintSearch(*queryMol, *fpGen, params);
CHECK(results.getHitMolecules().size() == 4);
for (const auto &r : results.getHitMolecules()) {
auto molWt = Descriptors::calcExactMW(*r);
CHECK((molWt >= 375.0 || molWt <= 390.0));
}
}
{
SynthonSpaceSearchParams params;
params.similarityCutoff = 0.45;
auto chiralQuery = "Cc1nccn1CCc1ccsc1COO[C@@H]1CCC[C@H](N)C1"_smiles;
results = synthonspace.fingerprintSearch(*chiralQuery, *fpGen, params);
CHECK(results.getHitMolecules().size() == 17);
params.minHitChiralAtoms = 1;
results = synthonspace.fingerprintSearch(*chiralQuery, *fpGen, params);
CHECK(results.getHitMolecules().size() == 11);
params.maxHitChiralAtoms = 1;
results = synthonspace.fingerprintSearch(*chiralQuery, *fpGen, params);
CHECK(results.getHitMolecules().size() == 4);
for (const auto &r : results.getHitMolecules()) {
auto numChiralAtoms = details::countChiralAtoms(*r);
CHECK((numChiralAtoms >= 1 && numChiralAtoms <= 3));
}
}
}
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