/**
* Fill in dependency list for all MathExpns on reactions.
* Note that when a MathExpn updates, it alters a further
* molecule, that may be a substrate for another reaction.
* So we need to also add further dependent reactions.
* In principle we might also cascade to deeper MathExpns. Later.
*/
void Gsolve::fillMathDep()
{
// create map of funcs that depend on specified molecule.
vector< vector< unsigned int > > funcMap( stoichPtr_->getNumAllPools());
unsigned int numFuncs = stoichPtr_->getNumFuncs();
for ( unsigned int i = 0; i < numFuncs; ++i ) {
const FuncTerm *f = stoichPtr_->funcs( i );
vector< unsigned int > molIndex;
unsigned int numMols = f->getReactants( molIndex );
for ( unsigned int j = 0; j < numMols; ++j )
funcMap[ molIndex[j] ].push_back( i );
}
// The output of each func is a mol indexed as
// numVarMols + numBufMols + i
unsigned int funcOffset =
stoichPtr_->getNumVarPools() + stoichPtr_->getNumBufPools();
unsigned int numRates = stoichPtr_->getNumRates();
sys_.dependentMathExpn.resize( numRates );
vector< unsigned int > indices;
for ( unsigned int i = 0; i < numRates; ++i ) {
vector< unsigned int >& dep = sys_.dependentMathExpn[ i ];
dep.resize( 0 );
// Extract the row of all molecules that depend on the reac.
const int* entry;
const unsigned int* colIndex;
unsigned int numInRow =
sys_.transposeN.getRow( i, &entry, &colIndex );
for ( unsigned int j = 0; j < numInRow; ++j ) {
unsigned int molIndex = colIndex[j];
vector< unsigned int >& funcs = funcMap[ molIndex ];
dep.insert( dep.end(), funcs.begin(), funcs.end() );
for ( unsigned int k = 0; k < funcs.size(); ++k ) {
unsigned int outputMol = funcs[k] + funcOffset;
// Insert reac deps here. Columns are reactions.
vector< int > e; // Entries: we don't need.
vector< unsigned int > c; // Column index: the reactions.
stoichPtr_->getStoichiometryMatrix().
getRow( outputMol, e, c );
// Each of the reacs (col entries) depend on this func.
vector< unsigned int > rdep = sys_.dependency[i];
rdep.insert( rdep.end(), c.begin(), c.end() );
}
}
}
}
//*--------------------------------------------------------------------------*//
//* MAIN MAIN *//
//*--------------------------------------------------------------------------*//
int main(int argc, char* argv[])
{
// Initialise random number generator
srandom(time(NULL));
clock_t t0 = clock();
// Print header
printHeader();
// Read options
Options uo = parseCommandLine(argc,argv);
if(!uo.noHybrid)
{
if(uo.funcGroupVec[AROM] && uo.funcGroupVec[LIPO])
{
uo.funcGroupVec[HYBL] = true;
}
if(uo.funcGroupVec[HDON] && uo.funcGroupVec[HACC])
{
uo.funcGroupVec[HYBH] = true;
}
}
std::cerr << uo.print() << std::endl;
if (uo.version)
{
printHeader();
exit(0);
}
if (uo.help)
{
printUsage();
exit(0);
}
// Db file and pharmacophore out are mandatory elements
if (uo.dbInpFile.empty())
{
mainErr("Missing database file. This is a required option (-d).");
}
if (uo.pharmOutFile.empty() && uo.molOutFile.empty() && uo.scoreOutFile.empty())
{
mainErr("No output file defined. So there is actually no use to compute anything at all.");
}
if ((uo.pharmOutFile.empty() && uo.scoreOutFile.empty()) && !uo.molOutFile.empty())
{
mainErr("No file defined to write pharmacophore information.");
}
if (uo.refInpFile.empty() && uo.pharmOutFile.empty() && uo.molOutFile.empty() && !uo.scoreOutFile.empty())
{
mainErr("Only score file requested when no reference is given. Unable to generate this output.");
}
// Reference variables
Pharmacophore refPharm;
refPharm.clear();
std::string refId;
double refVolume(0.0);
int refSize(0);
int exclSize(0);
// Database variables
std::vector<Result*> resList;
Pharmacophore dbPharm;
std::string dbId;
double dbVolume(0.0);
int dbSize(0);
//----------------------------------------------------------------------------
//...(A).. Process the reference
//----------------------------------------------------------------------------
if (!uo.refInpFile.empty())
{
//-------------------------------------------------------
//...(1).. get reference pharmacophore
//-------------------------------------------------------
if (uo.refInpType == UNKNOWN)
{
std::string ext(getExt(uo.refInpFile));
if (ext == ".phar")
{
uo.refInpType = PHAR;
}
else
{
uo.refInpType = MOL;
}
}
if (uo.refInpType == MOL)
{
OpenBabel::OBMol m;
OpenBabel::OBConversion* reader = new OpenBabel::OBConversion();
reader->SetInFormat(reader->FormatFromExt(uo.refInpFile.c_str()));
if (!reader->Read(&m, uo.refInpStream))
{
mainErr("Unable to read reference molecule");
}
calcPharm(&m, &refPharm, uo);
refId = m.GetTitle();
delete reader;
reader = NULL;
}
else if (uo.refInpType == PHAR)
{
PharmacophoreReader* reader = new PharmacophoreReader();
refPharm = reader->read(uo.refInpStream, refId);
if (refPharm.empty())
{
mainErr("Error reading reference pharmacophore");
}
delete reader;
reader = NULL;
}
else
{
mainErr("Unknown format of reference molecule.");
}
//-------------------------------------------------------
//...(2).. process reference pharmacophore
//-------------------------------------------------------
if (uo.merge)
{
pharMerger.merge(refPharm);
}
refSize = refPharm.size();
for (unsigned int i(0); i < refSize; ++i)
{
if (refPharm[i].func == EXCL)
{
// extract overlap with exclusion spheres
for (unsigned int j(0); j < refPharm.size(); ++j)
{
if (refPharm[j].func != EXCL)
{
refVolume -= VolumeOverlap(refPharm[i], refPharm[j], !uo.noNormal);
}
}
exclSize++;
}
else
{
// add point self-overlap
refVolume += VolumeOverlap(refPharm[i], refPharm[i], !uo.noNormal);
}
}
if(!uo.isQuiet)
{
std::cerr << "Reference pharmacophore " << refId << std::endl;
std::cerr << " number of points: " << refSize - exclSize << std::endl;
std::cerr << " number of exclusion spheres: " << exclSize << std::endl;
std::cerr << " totalvolume: " << refVolume << std::endl;
}
}
//----------------------------------------------------------------------------
//...(B).. Process the database file
//----------------------------------------------------------------------------
// DB files
if (uo.dbInpType == UNKNOWN)
{
std::string ext(getExt(uo.dbInpFile));
if (ext==".phar")
{
uo.dbInpType = PHAR;
}
else
{
uo.dbInpType = MOL;
}
}
// local storage of the rotation matrix
SiMath::Matrix rotMat(3,3,0.0);
unsigned int molCount(0);
OpenBabel::OBConversion* molReader = NULL;
PharmacophoreReader* pharmReader = NULL;
if (uo.dbInpType == PHAR)
{
pharmReader = new PharmacophoreReader();
}
else if (uo.dbInpType == MOL)
{
molReader = new OpenBabel::OBConversion();
molReader->SetInFormat(molReader->FormatFromExt(uo.dbInpFile.c_str()));
molReader->SetInStream(uo.dbInpStream);
}
else
{
mainErr("Unknown format of db file.");
}
bool done(false);
OpenBabel::OBMol m;
while (!done)
{
dbPharm.clear();
m.Clear();
if (uo.dbInpType == MOL)
{
if (!molReader->Read(&m))
{
done = true;
break;
}
else
{
calcPharm(&m, &dbPharm, uo);
dbId = m.GetTitle();
}
}
else
{
if (uo.dbInpStream->eof())
{
done = true;
break;
}
else
{
dbPharm = pharmReader->read(uo.dbInpStream, dbId);
}
}
if (dbPharm.empty())
{
continue;
}
++molCount;
if (!uo.isQuiet )
{
if ((molCount % 10) == 0)
{
std::cerr << "." << std::flush;
}
if ((molCount % 500) == 0)
{
std::cerr << molCount << std::endl << std::flush;
}
}
if (uo.merge)
{
pharMerger.merge(dbPharm);
}
if (uo.refInpFile.empty())
{
if (!(uo.isQuiet))
{
printProgress(molCount);
}
if( !uo.pharmOutFile.empty())
{
uo.pharmOutWriter->write(dbPharm, uo.pharmOutStream, dbId);
}
continue;
}
//-------------------------------------------------------
//...(1).. Alignment
//-------------------------------------------------------
dbSize = dbPharm.size();
dbVolume = 0.0;
for (unsigned int i(0); i < dbSize; ++i)
{
if (dbPharm[i].func == EXCL)
{
continue;
}
dbVolume += VolumeOverlap(dbPharm[i], dbPharm[i], !uo.noNormal);
}
// Create a result structure
Result res;
res.refId = refId;
res.refVolume = refVolume;
res.dbId = dbId;
res.dbVolume = dbVolume;
res.overlapVolume = 0.0;
res.exclVolume = 0.0;
res.resMol = m;
res.resPharSize = 0;
if (uo.scoreOnly)
{
FunctionMapping funcMap(&refPharm, &dbPharm, uo.epsilon);
PharmacophoreMap fMap = funcMap.getNextMap();
double volBest(-9999.999);
// loop over all reference points
while (!fMap.empty())
{
double newVol(0.0);
double exclVol(0.0);
for (PharmacophoreMap::iterator itP = fMap.begin(); itP != fMap.end(); ++itP)
{
if ((itP->first)->func == EXCL)
{
exclVol += VolumeOverlap((itP->first), (itP->second), !uo.noNormal);
}
else if (((itP->first)->func == (itP->second)->func ) ||
(((itP->first)->func == HYBH ||
(itP->first)->func == HDON ||
(itP->first)->func == HACC)
&& ((itP->second)->func == HDON ||
(itP->second)->func == HACC ||
(itP->second)->func == HYBH))
|| (((itP->first)->func == HYBL ||
(itP->first)->func == AROM ||
(itP->first)->func == LIPO)
&& ((itP->second)->func == AROM ||
(itP->second)->func == LIPO ||
(itP->second)->func == HYBL)))
{
newVol += VolumeOverlap((itP->first),(itP->second), !uo.noNormal);
}
}
if ((newVol - exclVol) > volBest)
{
res.resPhar.clear();
res.resPharSize = 0;
for (PharmacophoreMap::iterator itP = fMap.begin(); itP != fMap.end(); ++itP)
{
// add point to resulting pharmacophore
PharmacophorePoint p(itP->second);
(res.resPhar).push_back(p);
++res.resPharSize;
}
res.overlapVolume = newVol;
res.exclVolume = exclVol;
volBest = newVol - exclVol;
}
// get the next map
fMap.clear();
fMap = funcMap.getNextMap();
}
}
else
{
FunctionMapping funcMap(&refPharm, &dbPharm, uo.epsilon);
PharmacophoreMap fMap = funcMap.getNextMap();
PharmacophoreMap bestMap;
// default solution
SolutionInfo best;
best.volume = -999.9;
// rotor is set to no rotation
best.rotor.resize(4);
best.rotor = 0.0;
best.rotor[0] = 1.0;
double bestScore = -1000;
int mapSize(fMap.size());
int maxSize = mapSize - 3;
while (!fMap.empty())
{
int msize = fMap.size();
// add the exclusion spheres to the alignment procedure
if (uo.withExclusion)
{
for (unsigned int i(0); i < refSize ; ++i)
{
if (refPharm[i].func != EXCL)
{
continue;
}
for (unsigned int j(0); j < dbSize; ++j)
{
if (dbPharm[j].func == EXCL)
{
continue;
}
fMap.insert(std::make_pair(&(refPharm[i]), &(dbPharm[j])));
}
}
}
// Only align if the expected score has any chance of being larger
// than best score so far
if ((msize > maxSize)
&& (((double) msize / (refSize - exclSize + dbSize - msize)) > bestScore))
{
Alignment align(fMap);
SolutionInfo r = align.align(!uo.noNormal);
if (best.volume < r.volume)
{
best = r;
bestScore = best.volume / (refVolume + dbVolume - best.volume);
bestMap = fMap;
mapSize = msize;
}
}
else
{
// Level of mapping site to low
break;
}
if (bestScore > 0.98)
{
break;
}
// Get the next map
fMap.clear();
fMap = funcMap.getNextMap();
}
// Transform the complete pharmacophore and the molecule towards the
// best alignment
rotMat = quat2Rotation(best.rotor);
positionPharmacophore(dbPharm, rotMat, best);
positionMolecule(&res.resMol, rotMat, best);
// Update result
res.info = best;
// Compute overlap volume between exlusion spheres and pharmacophore
// points
for (int i(0); i < refSize; ++i)
{
if (refPharm[i].func != EXCL)
{
continue;
}
for (int j(0); j < dbSize; ++j)
{
res.exclVolume += VolumeOverlap(refPharm[i], dbPharm[j], !uo.noNormal);
}
}
// make copy of the best map and compute the volume overlap
for (PharmacophoreMap::iterator itP = bestMap.begin(); itP != bestMap.end(); ++itP)
{
if(((itP->first)->func == EXCL) || ((itP->second)->func == EXCL))
{
continue;
}
// compute overlap
res.overlapVolume += VolumeOverlap(itP->first, itP->second, !uo.noNormal);
// add point to resulting pharmacophore
PharmacophorePoint p(itP->second);
(res.resPhar).push_back(p);
++res.resPharSize;
}
}
// update scores
res.info.volume = res.overlapVolume - res.exclVolume;
if (res.info.volume > 0.0)
{
res.tanimoto = res.info.volume / (res.refVolume + res.dbVolume - res.info.volume);
res.tversky_ref = res.info.volume / res.refVolume;
res.tversky_db = res.info.volume / res.dbVolume;
}
switch (uo.rankby)
{
case TANIMOTO:
res.rankbyScore = res.tanimoto;
break;
case TVERSKY_REF:
res.rankbyScore = res.tversky_ref;
break;
case TVERSKY_DB:
res.rankbyScore = res.tversky_db;
break;
}
//-------------------------------------------------------
//...(5).. Generate output
//-------------------------------------------------------
if (uo.cutOff != 0.0)
{
if (res.rankbyScore < uo.cutOff)
{
continue;
}
}
if (uo.best != 0)
{
addBest(res, uo, resList);
}
else
{
if (!uo.molOutFile.empty())
{
logOut(&res, uo);
}
if (!uo.pharmOutFile.empty())
{
logPharmacophores(&res, uo);
}
if (!uo.scoreOutFile.empty())
{
logScores(&res, uo);
}
}
}
if (molReader)
{
delete molReader;
molReader = NULL;
}
if (pharmReader)
{
delete pharmReader;
pharmReader = NULL;
}
//----------------------------------------------------------------------------
//...(C).. Process best list (if defined)
//----------------------------------------------------------------------------
if (uo.best != 0)
{
std::vector<Result*>::iterator itR;
for (itR = resList.begin(); itR != resList.end(); ++itR)
{
Result* res(*itR);
if (!uo.molOutFile.empty())
{
logOut(res, uo);
}
if (!uo.pharmOutFile.empty())
{
logPharmacophores(res, uo);
}
if (!uo.scoreOutFile.empty())
{
logScores(res, uo);
}
delete res;
}
}
// done processing database
if (!uo.isQuiet)
{
if (uo.refInpFile.empty())
{
std::cerr << std::endl;
std::cerr << "Processed " << molCount << " molecules";
double tt = (double)(clock() - t0 )/CLOCKS_PER_SEC;
std::cerr << " in " << tt << " seconds (";
std::cerr << molCount/tt << " molecules per second)." << std::endl;
}
else
{
std::cerr << std::endl;
std::cerr << "Processed " << molCount << " molecules" << std::endl;
double tt = (double)(clock() - t0 )/CLOCKS_PER_SEC;
std::cerr << molCount << " alignments in " << tt << " seconds (";
std::cerr << molCount/tt << " alignments per second)." << std::endl;
}
}
exit(0);
}