11 Toolkits. What can you do with them?

11 Toolkits. What can you do
with them?
Phillip Sawunyama
EuroCUP IV, April 2010

Who is having fun?

Who is having fun?

Molecular modeling Cheminformatics
Zap TK
Poisson-Boltzmann electrostatics
solver
Spicoli TK
Molecular surfaces & volume
generation
SzybkiTK
General purpose function
optimization
Quacpac TK
Tautomer/Protomer enumeration
& charge assignment
Shape TK
Molecular descriptors for shape
overlay & similarity
OmegaTK
Conformer ensembles containing
bioactive conformations
Docking TK
Docking ligands into a receptor
OEChem TK
Programming library for
chemistry and
cheminformatics
GraphSim TK
Fingerprints for 2D similarity
MolProp TK
Molecular property calculation
Lexichem/OEIUPAC TK
Conversion of chemical names to
chemical structures & vice-versa
Ogham/OEDepict TK
2D Molecular Drawings Rendering

OEMath
Geometry Handling,
Constants
OEBio
Sequence Alignment,
Crystal Symmetry
OEChem TK
(1.7.2)
Required in order to use other
toolkits
OEChem
Molecules, File Formats,
Searching
OEGrid
Data container for points
in 3D lattice
OEPlatform
IO, Synchronization,
Machine Info
OESystem
Error Handling, Data
Structures

If you just have OEChem…
• Data Processing
– SD data handling
– Small in-memory molecules
• 2D
– Exact and Maximum common substructure
– LINGOS
– Normalization
– Library Generation
• 3D
– Conformers
– Translation/Rotation/Torsions
– RMSD fitting (including automorphisms)

OEChem: Molecules
• Easy way to manage molecules, atoms,
bonds, conformers, queries, and reactions.
• Iterators for traversing atoms and bonds
for atom in mol.GetAtoms():
for bond in atom.GetBonds():
print atom.GetName(), bond.IsRotor()

OEChem file format conversion
SMILES MOL2 SDF PDB OEB
Daylight
Chemistry
Tripos
Chemistry
MDL
Chemistry
PDB
Chemistry
OpenEye
Chemistry
• Aromaticity, valence model, kekulization, atom-types & implicit H’s

Multiple aromaticity models
MDL
Yes
No
No
No
No
Tripos
Yes
No
No
N/A
No
MMFF
Yes
Yes
No
N/A
No
Daylight
Yes
Yes
Yes
No
No/Yes
OpenEye
Yes
Yes
Yes
Yes
Yes
OEAssignAromaticFlags(mol, OEAroModelTripos)

High Level and Low Level
High Level Low Level
High Level
OEWriteMolecule(ifs,mol)
Low Level
OECreateSmiString(str,mol,AtomMap|Kekule|Canonical)

Simple File Conversion Example
Import sys
from openeye.oechem import *
ifs = oemolistream(sys.argv[1])
ofs = oemolostream(sys.argv[2])
for mol in ifs.GetOEGraphMols():
OEWriteMolecule(ofs, mol)
Open Input &
output streams
Write out data
OEWriteMolecule function will change your molecules.
Use OEWriteConstMolecule function if you do not want your
molecules to change.

Canonical Isomeric SMILES
Solved problems
(R)
(S)
CC([C@@H](C)N)[C@H](C)N
CC([C@H](C)N)[C@@H](C)N
Test set (10M)
(bond or atom stereo)
78 failures
C/C=C/C=C\C
C/C=C\C=C\C
reordering atoms
(10 times/compound)
C1C[C@@H](CC[C@@H]1O)O
C1C[C@H](CC[C@H]1O)O
C1C[C@H](CC[C@@H]1O)O
C1C[C@@H](CC[C@H]1O)O

SD Data Manipulation
• Get Data, Change Data, Set Data
• SDF and OEB files
Registry Number
Binding Energy
CYP 3A4 Data

Simple SDData Example
ifs = oemolistream(sys.argv[1])
ofs = oemolostream(sys.argv[2])
mol = OEGraphMol()
while OEReadMolecule(ifs, mol):
id = OEGetSDData(mol, “ID”)
id = “OpenEye” + id;
OESetSDData(mol, “ID”, id)
OEWriteMolecule(ofs, mol)
Get Data
Change Data
Set Data

Small in-memory molecules
• OEMolBase::Compress
• OEMolBase::UnCompress
• MiniMol
– Graph only
– Only call Compress once
• DBMols – can be even smaller
– Coordinates and all
– Call UnCompress and Compress every time

Substructure Search
• Loop through a database writing out matches
Define a function for initializing substructure search
def SubSearch(ifs,ofs, qmol):
subsearch = OESubSearch()
atomexpr = OEExprOpts_DefaultAtoms
bondexpr = OEExprOpts_DefaultBonds
if not subsearch.Init(qmol, atomexpr, bondexpr ):
OEThrow.Fatal(“Unable to initialize substructure search”)
for mol in ifs.GetOEGraphMols():
if subsearch.SingleMatch(mol):
OEWriteMolecule(ofs, mol)

MDL Query File Support

Maximum Common Substructure
Search
• Maximum common substructure searches can be performed in
OEChem using the OEMCSSearch class. The OEMCSSearch
class can be initialized with a SMARTS pattern, an
OEQMolBase query molecule, or a molecule with expression
options.

Pro:
- guaranteed to find
the maximum common
substructure(s)
Con:
- complex structures
can not be mapped
efficiently
Exhaustive MCSS
for each matching
atom pair
…
…
…
?
? ?
common sub-graph
can not be extended
any more
?
evaluate
…
extend
subgraph
all
possible
ways

pre-defined paths in the pattern
…
Approximate MCSS
…
try to follow the same path in
the target
!

Clique Search
Can also perform a clique search using the
OECliqueSearch class.
Identify all common substructures between a
reference molecule and a target molecule

Generate Molecular Framework
Morphine Scaffold or reduced graph

OEChem: Normalization
Uses SMIRKS to specify normalization
!"#$%$&'()*+,-./!-0#12)3456789:;

Inter-conversion of the nitro group
The nitro group is typically represented either with pentavalent Nitrogen
“*N(=O)=O” or as a charge-separated trivalent Nitrogen “*[N+](=O)[O-]”
SMIRKS PATTERN
To convert to the trivalent form:
"[*:1][N:2](=[O:3])=[O:4]>>[*:1][N+:2](=[O:3])[O-:4]"
To convert to the pentavalent form:
"[*:1][N+:2]([O-:3])=[O:4]>>[*:1][N+0:2](=[O+0:3])=[O:4]"

Library Generation
Supported MDL query features
• generic and alternative atom types
• number of substituents, ring bonds, hydrogens
• unsaturated atom
• alternative bond types, topology, stereo care
substructure
search
amide.rxn
transformation

Conformers and Geometry
• Easy handling of multi-conformer molecules
• Torsions
• Translations
• Rotations
• Moments of inertia
• RMSD: Automatically handles automorphisms

OEGrid
• Bundled with OEChem
• Supports lattices as first class objects
– OEScalarGrid
– OESkewGrid
• Features
– IO from several formats (gridbabel)
– Attach as generic data to molecules
– Regularization
– Masking
– Interpolation

Wedge bond direction
• Clean up structures with
incorrectly assigned bond
stereochemistry (common
problem). The narrow end of the
wedge bond is incorrectly oriented
toward an sp 2
• The bond stereo specified by the
MD/SDF file is stored as generic
data on the bond using the
"OEProperty_BondStereo" tag.

• Demo!
Wedge bond direction
• This corrects the bond direction when it's obviously wrong.
However, there are cases, such as when both atoms of a bond
are chiral, when the direction can not be automatically
corrected. In these cases the program only gives a warning
but leaves the bond direction unchanged.

• Hierarchy View
OEBIO
– represent a biopolymer molecule as a hierarchy of
the components: OEHierChain, OEHierFragment,
and OEHierResidue.
• Extract Ligand from a protein-ligand complex
• Extract protein backbone
• Calculate phipsi rotatable angles for residues --
Ramachandran plot
• Alternate locations
• Sequence alignment

! of PDB Structures Contain
Alternate Location Codes
• Not molecules but
ensembles
• To compute molecular
properties, must
restrict to subset of
atoms
– (eg. just the ‘A’s)

OEBIO
• Create a subset of residues (demo)

The shape toolkit
• Greatly simplifies some tasks
– Using multiple queries
• Exclusions
– Using different color files in the same run
• Filtering with constraints
• Some tasks that cannot be done in ROCS
– NxN comparisons/clustering
– Shape multipoles

OEQuacPac & OESzybki
• On-the-fly protonation state sampling
– Load protein and ligand
– OEAddExplicitHydrogens
– Loop over pka and tautomer states
• OESet3DHydrogenGeom
• Perform Szybki minimization
– Write out the state with the best score

• Surfaces
– Molecular
– Accessible
– Primitives
• Properties
– Area
– Volume
• Void volume
– Curvature
– Depth
OESpicoli

Calculate binding site surface

Calculate binding site surface

ZAP: PB Electrostatics
• Solvation energy & potential grids:
– zap.CalcSolvationEnergy()
– zap.CalcPotentialGrid()
• Both properties on a grid
• Accessible surface area: OEArea
• Binding properties: OEBind
– OEBindResults() allows dissection of all components
• Electrostatic similarity: OEET
– In situ calculation of electrostatic Tanimoto

OEIUPAC (Lexichem)
• The Languages of Chemistry
Images
Names Structures
Methylsalicylate/
2-methoxybenzoate
COc1ccccc1C(=O)[O-]

Lexichem: Naming
• Names structures
– Multi-language support
• German, Japanese, Welsh, Klingon...
• 100% round-trip translation
• Name -> structure -> name
– 250,000 NCI screening database
– 92.5% round-trip
DOI: 10.1021/ci800243w; J. Chem. Inf. Model., 49, 519 (2009)

Naming and Depiction (OEDepict)
benzene
nam2mol
mol2nam
c1ccccc1
depict
mol2gif
Lexichem Ogham
-OEChem-05210615262D
6 6 0 0 0 0 0 0 0999 V2000
-0.8674 1.5027 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0
-0.8674 0.4976 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0
0.0000 0.0000 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0
0.8674 0.4976 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0
0.8674 1.5027 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0
0.0000 2.0102 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0
1 6 2 0 0 0 0
1 2 1 0 0 0 0
2 3 2 0 0 0 0
3 4 1 0 0 0 0
4 5 2 0 0 0 0
5 6 1 0 0 0 0
M END

Picto
• Depiction/naming tool
– OEChem + Lexichem + Ogham
• Ships with toolkits and also with VIDA 4.0, must be
compiled (C++)
• SMILES name
– Structure is depicted
• Atom selection -> SMARTS

Picto

• OEGraphSim Fingerprints
– MACCS
– LINGO
– Path-based
• Storing Fingerprints
• Similarity Search using OEFPDatabase
• Performance & validation
• Fingerprint Similarity Measures
– Built-in, user-defined
• User-defined path fingerprint

• 166 bit fingerprint
• Each bit is associated with a predefined SMARTS pattern
MACCS FP generation =
substructure search
OEMakeFP(fp, mol, OEFPType_MACCS166)
OEMakeMACCS166FP(fp, mol)
…
…

• Based on the fragmentation of canonical isomeric SMILES
into overlapping substrings
• Similarity concept (similar SMILES equal similar structures)
LINGO FP generation =
SMILES generation
OEMakeFP(fp, mol, OEFPType_Lingo)
OEMakeLingoFP(fp, mol)
c1cc([nH]c1)N c1cc([nH]c1)O

• No predefined pattern dictionary
• Exhaustively enumerate all paths in a molecule
Path FP generation =
enumerating paths
+ hashing
OEMakeFP(fp, mol, OEFPType_Path)
OEMakePathFP(fp, mol)
collision

Size in Mbyte
:AA$
DA$
CA$
BA$
8A$
A$
MACCS
LINGO
PATH
RSS
OEB
OEB GZ
• Dataset MDDR
(~110,000 compounds)
OEB GZ
OEB
RSS
• OEB GZ, OEB (disk space)
• RSS (size in physical memory)
– Using compressed OEDBMols
• Path FPs are generated with
default parameters
– 4096 bit fingerprint
Estimated memory usage
for 1M compounds
MACCS LINGO PATH
430M 470M 900M

Time in sec
:AA$
FE$
EA$
8E$
A$
+GHHI$
JK6L&$
• Dataset: MDDR (~110,000)
• Path FPs with default parameters
– 4096 bit fingerprint
– 0-5 path lengths
MGN7$
Core
XEON
• Intel® Core 2
Quad CPU Q6600
(2.4 GHz)
• Intel® XEON®
CPU X5560
(2.8 GHz)
Estimated time to
generate FP for 1M
compounds (ISM!OEB)
MACCS LINGO PATH
~12min ~2min ~5min

OEMolProp
• Calculates 2D molecular properties
• XlogP
• XlogS
• PSA
• hydrogen bond donor and acceptor count
• rotatable bonds, ring size and number
• Generates custom filters
• ADME filters such as Lipinski
• Provides graph-based protonation state assignment
for consistency and speed

Link OE Libraries: DEMO
1. Link Libraries
sys, oechem, oeiupac, oeomega, oegrid
2. Open output streams
sys
3. Read compound names (iupac) from a text file and convert names to structures.
sys, oeiupac
4. Count Rotors
oechem
5. Generate Conformers
oeomega
6. Generate Grid and Write Output
oegrid, oechem

Examples built on OEChem
• Registry Systems
• Pharmacophore tools
• PubChem
• Mix and match
– Rpy
– Database cartridges
– Web services

Give your users this UI
Designing the application UI
Now that you’re armed with your 11 toolkits…
And not this UI

For more information, please contact us.
business@eyesopen.com
support@eyesopen.com
www.eyesopen.com
505-473-7385
That’s it folks!
• http://www.eyesopen.com/docs/: Toolkit Manuals with code examples (C++, Python, Java)
• ~/openeye/toolkits/examples (C++)
• ~/openeye/python/examples (Python)
• ~/openeye/java/openeye/examples (Java)