Transcript ChemAxon in 3D Gábor Imre, Adrián Kalászi and Miklós Vargyas Solutions for Cheminformatics.

ChemAxon in 3D
Gábor Imre, Adrián Kalászi and Miklós Vargyas
Solutions for Cheminformatics
Talk overview
• ChemAxon’s 2D tradition
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–
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visualize
depict/edit
search
calculate/predict properties
• 3D pearls
3D visualization
3D structure generation
3D search
• And what do we do with 3D structures?
• Like what, why, give motivation
• Perhaps we can show some cars without
going to details, just en passant
• But we may refer to shapes
Advanced 3D visualization
3D structure generation
• Why is 3D structure generation hard
• What are the typical approaches
Our approach
• Chemically aware coordinate and conformer
generation
• Reliable, robust
Searching in 3D
• Molecules are inherently spatial objects
• Typical searches are two-dimensional
– Molecular descriptor
– Fingerprint
3D alignment
Conformational flexibility
Multi-conformer rigid search
• One viable solution to tackle conformational
flexibility
• The rigid apparatus can be applied
• Highly combinatorial:
– All target conformation need to be considered
– Do we have multiple query conformations?
• multiple conformations have to be generated
Multiple conformation generation
• Molecular mechanics based geometry
optimization
– Improved Dreiding force field to suite wider range
of (small organic) molecules
– Modified to support efficient optimization
– Fast numeric optimization
3D alignment
• Minimizes atom-pair distance constraints
0.7
0.6
pot. function value
0.5
0.4
0.3
0.2
0.1
0
0
1
2
3
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distance (Angstrom)
6
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10
Alignment of challenging molecules
3D shape similarity
T=
+
-
3D virtual screening
• 3D flexible virtual screening on 2D
molecules with 2D query
• Maximizes colored shape intersection of the
query and the target
• Calculates volume Tanimoto of the optimum
3D flexible alignment
3D pharmacophore fingerprint
3D pharmacophore fingerprint
Summary
• 3D molecule alignment
– Rigid – all conformations are intact
– Flexible – all conformations may change
– Combined – only the selected molecules are
rigid, the others treated flexible
– Atom pairing
• User defined
• Auto align – tries to find the optimal overlay
• Combined
– Chemically sound conformations
– Optional ring flexibility
Summary
• 3D virtual screening
– Minimal and maximal interatomic distances are
calculated between atoms of given types
– The costly calculation of the fingerprint is done
only once per library
– The similarity search is as fast as with 2D
fingerprint
– All the popular similarity functions can be
calculated: Tanimoto, Tversky, Dice, Euclidean.
MD
Simple dreiding based MD
• Used internally by hyperfine
• Available as a plugin also
Projected MD
• In development
• Rigid term energy redistribution
• Extremely fast conformational transitions due
to the elimination of vibrational components
3D calculations
Conformers plugin
• Coordinate / conformers generation
• Geometry optimization
• Energy calculation
Geometry plugins
• Steric hindrance
• Molecular surface area
• Molecular projection area
• Molecular volume
Acknowledgement
• Dr. Ödön Farkas
• Dr. Imre Jákli
• Judit Vasko-Szedlar