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brownbp1/addmedchem_element_liberty #4

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3a5e23f
Added support for users to specify their own dummy element types for …
brownbp1 Jun 17, 2022
1cb35a7
Fixed a bunch of atom selection bugs from the last commit.
brownbp1 Jun 21, 2022
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7 changes: 7 additions & 0 deletions include/chemistry/bcl_chemistry_fragment_add_med_chem.h
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Original file line number Diff line number Diff line change
Expand Up @@ -68,9 +68,16 @@ namespace bcl
util::ShPtr< FragmentEnsemble> m_FragmentPool;
std::string m_MedChemFilename;

//! alternate element types to Undefined to control directionality
std::string m_MedChemFragmentLinkElementType;
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@jeffmendenhall jeffmendenhall Jun 26, 2022

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Why aren't these chemistry::ElementType ? or lists of them if that's more appropriate?
Not that performance is an issue here, but it does lots of needless lookups later where it would seem better to just have an element type instance unless I'm missing something

std::string m_TargetMoleculeLinkElementType;

//! restrict medchem additions to aromatic rings
bool m_RestrictAdditionsToAroRings;

//! must use this flag if you want to specify an element type as a dummy atom
bool m_EnableDummyAtom;

//////////
// data //
//////////
Expand Down
184 changes: 178 additions & 6 deletions source/chemistry/bcl_chemistry_fragment_add_med_chem.cpp
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Expand Up @@ -21,6 +21,7 @@ BCL_StaticInitializationFiascoFinder

// includes from bcl - sorted alphabetically
#include "chemistry/bcl_chemistry_atoms_complete_standardizer.h"
#include "chemistry/bcl_chemistry_element_types.h"
#include "chemistry/bcl_chemistry_fragment_map_conformer.h"
#include "chemistry/bcl_chemistry_fragment_track_mutable_atoms.h"
#include "chemistry/bcl_chemistry_hydrogens_handler.h"
Expand Down Expand Up @@ -240,6 +241,59 @@ namespace bcl
// mutate label
BCL_MessageStd( "AddMedChem!");

// this will cause issues so it's banned
if
(
( m_TargetMoleculeLinkElementType.empty() && m_EnableDummyAtom ) ||
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@jeffmendenhall jeffmendenhall Jun 26, 2022

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Why not just have m_EnableDummyAtom=!m_TargetMoleculeLinkElementType.empty(); in the rest of the logic. If I give a list of linked element types, it seems I must want them, no?

( !m_TargetMoleculeLinkElementType.empty() && !m_EnableDummyAtom )
)
{
BCL_MessageStd
(
"\n"
"Invalid combination of target molecule atom selection options. "
"To obtain pseudo-reaction-style control over the reaction without "
"specifying specific atom indices, the following options are available: \n"
"1. Set 'mutable_elements=X', do not specify any other atom selectors. \n"
"2. Choose an element type that is unique in the target molecule, such as "
"Rb, set 'mutable_elements=Rb', 'target_molecule_link_element=Rb', and "
"'enable_target_dummy_atom=true'. \n"
"For either option 1 or 2, you are free to change the link/dummy element type "
"of the medchem fragments via the 'medchem_fragment_link_element' flag depending "
"on how your library is constructed."
"\n"
);
return math::MutateResult< FragmentComplete>( util::ShPtr< FragmentComplete>(), *this);
}
else if
(
!m_TargetMoleculeLinkElementType.empty() &&
m_EnableDummyAtom &&
m_MutableElements.Find( GetElementTypes().ElementTypeLookup( m_TargetMoleculeLinkElementType)) >= m_MutableElements.GetSize()
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@jeffmendenhall jeffmendenhall Jun 26, 2022

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Once you make those variables element types or lists thereof, can remove the elementtypelookup here

)
{
BCL_MessageStd
(
"\n"
"A custom target molecule link element type was specified and enabled, but "
"the input molecule does not contain any elements of the desired type. "
"Alternatively, the specified element type is mismatched with the allowed mutable "
"element types."
"\n"
);
return math::MutateResult< FragmentComplete>( util::ShPtr< FragmentComplete>(), *this);
}

// get connecting element types
const ElementType medchem_fragment_link_element
(
m_MedChemFragmentLinkElementType.empty() ? GetElementTypes().e_Undefined : GetElementTypes().ElementTypeLookup( m_MedChemFragmentLinkElementType)
);
const ElementType target_molecule_link_element
(
m_TargetMoleculeLinkElementType.empty() ? GetElementTypes().e_Undefined : GetElementTypes().ElementTypeLookup( m_TargetMoleculeLinkElementType)
);

Comment on lines +288 to +296
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@jeffmendenhall jeffmendenhall Jun 26, 2022

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This logic would also be unnecessary if they are just element types or lists thereof, whichever is appropriate

// redo the whole thing n-max times; increment can also be made in an inner while-loop during atom index selection
size_t try_index( 0);
for( ; try_index < m_NumberMaxAttempts; ++try_index)
Expand All @@ -256,16 +310,34 @@ namespace bcl
size_t undefined_index( util::GetUndefinedSize_t());
for( size_t i( 0), end_i( medchem_atom_v.GetSize()); i < end_i; ++i)
{
if( medchem_atom_v( i).GetElementType() == GetElementTypes().e_Undefined)
if( medchem_atom_v( i).GetElementType() == medchem_fragment_link_element)
{
undefined_index = i;
break;
}
}
if( undefined_index == util::GetUndefinedSize_t())
{
return math::MutateResult< FragmentComplete>( util::ShPtr< FragmentComplete>(), *this);
}

// dummy atoms are allowed only one bonded partner, which must be a heavy atom
BCL_Assert
(
medchem_atom_v( undefined_index).GetBonds().GetSize() == size_t( 1),
"Encountered a medchem fragment from the library whose target link atom "
"contains more than one bond! This is not allowed. Atoms designating "
"pseudo-reactions must be bonded to only one heavy atom. Exiting..."
);

BCL_Assert
(
medchem_atom_v( undefined_index).GetBonds().Begin()->GetTargetAtom().GetElementType() != GetElementTypes().e_Hydrogen,
"Encountered a medchem fragment from the library whose target link atom "
"is bonded to a hdyrogen atom. This is not allowed. Atoms designating "
"pseudo-reactions must be bonded to only one heavy atom. Exiting..."
);

// get the element to which the reactive atom is bonded
auto &atom_bonded_to_undefined( medchem_atom_v( undefined_index).GetBonds().Begin()->GetTargetAtom());
size_t atom_bonded_to_undefined_index( medchem_atom_v.GetAtomIndex( atom_bonded_to_undefined));
Expand All @@ -278,7 +350,12 @@ namespace bcl
storage::Vector< size_t> defined_indices;
for( size_t i( 0), end_i( medchem_atom_v.GetSize()); i < end_i; ++i)
{
if( medchem_atom_v( i).GetElementType() != GetElementTypes().e_Undefined)
if
(
// remove undefined elements anyway, even if we use a separate link element type
medchem_atom_v( i).GetElementType() != GetElementTypes().e_Undefined &&
i != undefined_index
)
{
defined_indices.PushBack( i);
}
Expand Down Expand Up @@ -309,9 +386,33 @@ namespace bcl
// if the chosen atom is undefined then just grab a bonded atom
// this is biased to the lower index bonded atom, but should not generally matter
size_t undefined_base_index( util::GetUndefinedSize_t());
if( picked_atom->GetElementType() == GetElementTypes().e_Undefined)
if
(
picked_atom->GetElementType() == GetElementTypes().e_Undefined ||
( picked_atom->GetElementType() == target_molecule_link_element && m_EnableDummyAtom )
)
{
// this is the dummy atom
undefined_base_index = FRAGMENT.GetAtomVector().GetAtomIndex( *picked_atom);

// dummy atoms are allowed only one bonded partner, which must be a heavy atom
BCL_Assert
(
FRAGMENT.GetAtomVector()( undefined_base_index).GetBonds().GetSize() == size_t( 1),
"The user atom selection specified a target atom dummy atom for linking "
"that contains more than one bond! This is not allowed. Atoms designating "
"pseudo-reactions must be bonded to only one heavy atom. Exiting..."
);

BCL_Assert
(
FRAGMENT.GetAtomVector()( undefined_base_index).GetBonds().Begin()->GetTargetAtom().GetElementType() != GetElementTypes().e_Hydrogen,
"The user atom selection specified a target atom dummy atom for linking "
"that is bonded to a hydrogen atom! This is not allowed. Atoms designating "
"pseudo-reactions must be bonded to only one heavy atom. Exiting..."
);

// reassign picked atom to the atom bonded to the dummy atom
picked_atom = util::SiPtr< const AtomConformationalInterface>( picked_atom->GetBonds().Begin()->GetTargetAtom());
}

Expand Down Expand Up @@ -353,9 +454,33 @@ namespace bcl
picked_atom = this->PickAtom( FRAGMENT, true);
}

if( picked_atom->GetElementType() == GetElementTypes().e_Undefined)
if
(
picked_atom->GetElementType() == GetElementTypes().e_Undefined ||
( picked_atom->GetElementType() == target_molecule_link_element && m_EnableDummyAtom )
)
{
// this is the dummy atom
undefined_base_index = FRAGMENT.GetAtomVector().GetAtomIndex( *picked_atom);

// dummy atoms are allowed only one bonded partner, which must be a heavy atom
BCL_Assert
(
FRAGMENT.GetAtomVector()( undefined_base_index).GetBonds().GetSize() == size_t( 1),
"The user atom selection specified a target atom dummy atom for linking "
"that contains more than one bond! This is not allowed. Atoms designating "
"pseudo-reactions must be bonded to only one heavy atom. Exiting..."
);

BCL_Assert
(
FRAGMENT.GetAtomVector()( undefined_base_index).GetBonds().Begin()->GetTargetAtom().GetElementType() != GetElementTypes().e_Hydrogen,
"The user atom selection specified a target atom dummy atom for linking "
"that is bonded to a hydrogen atom! This is not allowed. Atoms designating "
"pseudo-reactions must be bonded to only one heavy atom. Exiting..."
);

// reassign picked atom to the atom bonded to the dummy atom
picked_atom = util::SiPtr< const AtomConformationalInterface>( picked_atom->GetBonds().Begin()->GetTargetAtom());
}

Expand Down Expand Up @@ -425,7 +550,7 @@ namespace bcl
AtomVector< AtomComplete> all_defined_atom_v( FRAGMENT.GetAtomVector());
all_defined_atom_v.Reorder( keep_indices);
AtomsCompleteStandardizer standardizer_2( all_defined_atom_v, "", true);
standardizer.SetConjugationOfBondTypes( all_defined_atom_v);
standardizer_2.SetConjugationOfBondTypes( all_defined_atom_v);

// make new fragment
FragmentComplete fragment( all_defined_atom_v, FRAGMENT.GetName());
Expand Down Expand Up @@ -521,7 +646,19 @@ namespace bcl
io::Serializer parameters( FragmentMutateInterface::GetSerializer());
parameters.SetClassDescription
(
"Appends a classic medicinal chemistry functional group to the current molecule"
"Appends a classic medicinal chemistry functional group to the current molecule. "
"By default, fragments passed with the 'medchem_library' flag will be appended "
"to the input "
"molecule; "
"To obtain pseudo-reaction-style control over the reaction without "
"specifying specific atom indices, the following options are available: "
"1. Set 'mutable_elements=X', do not specify any other atom selectors. "
"2. Choose an element type that is unique in the target molecule, such as "
"Rb, set 'mutable_elements=Rb', 'target_molecule_link_element=Rb', and "
"'enable_target_dummy_atom=true'. "
"For either option 1 or 2, you are free to change the link/dummy element type "
"of the medchem fragments via the 'medchem_fragment_link_element' flag depending "
"on how your library is constructed."
);

parameters.AddInitializer
Expand All @@ -540,6 +677,41 @@ namespace bcl
"false"
);

parameters.AddInitializer
(
"medchem_fragment_link_element",
"alternative link element type for the medchem fragments; if unspecified, defaults to "
"the undefined element type (X). "
"Dummy/linker atoms are required to have only one bond to the target atom of interest. ",
io::Serialization::GetAgent( &m_MedChemFragmentLinkElementType),
"X"
);

parameters.AddInitializer
(
"target_molecule_link_element",
"alternative link element type for the input molecules; "
"if you are not using an undefined element (specific 'X' in SDF) to mark the attachment site "
"by specifying 'mutable_elements=X', then use this flag to change the element type; "
"requires that 'enable_target_dummy_atoms' is set; "
"be careful that this is applied appropriately with the mutable_elements atom selector "
"Dummy/linker atoms are required to have only one bond to the target atom of interest. ",
io::Serialization::GetAgent( &m_TargetMoleculeLinkElementType),
""
);

parameters.AddInitializer
(
"enable_target_dummy_atom",
"allows users to specify dummy element types other than undefined (X) for directed "
"pseudo-reaction-style attachment of medchem fragments; "
"by default if 'mutable_elements' is set to X and no other atom selectors are specified "
"then only X elements will 'react' with the link element type in the medchem library "
"fragments (default is also X). ",
io::Serialization::GetAgent( &m_EnableDummyAtom),
"0"
);

return parameters;
}

Expand Down