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Computer-Chemie-Centrum Universität Erlangen-Nürnberg
Virtual screening and modelling: must it be
atoms?
Virtual screening and modelling: must it be
atoms?Tim Clark
Computer-Chemie-Centrum
Universität Erlangen-Nürnberg
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
What are molecules?What are molecules?
C
H
O
H
H
H
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
Atoms in molecules (AIM)Atoms in molecules (AIM)
• An approximation that relies on the transferability of properties of atoms and groups between molecules
• This requires transferability of the electron density assignable to an atom or group• Follows from the first Hohenberg-Kohn theorem• Made popular in the ab initio community by
Richard Bader
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
AIM in virtual screening AIM in virtual screening and modellingand modelling
• Fingerprints• Fragment models• Similarity (usually)• Topological indices and descriptors• Graph theory• Atomic charge models• Force fields• Scoring functions• Generalised Born solvation models
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
AIM in scoring functionsAIM in scoring functions
2 2 2H O H O H O
Enzyme Ligand Enzyme Ligand
2 2nH O n x H OEnzyme Enzyme
2 2mH O m y H OLigand Ligand
2 2n x H O m y n m x y H O
Enzyme Ligand Enzyme Ligand
. . :enzyme ligand
bind desolv desolv ligand enzymeG G G G
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
Scoring functionsScoring functions• Desolvation free energies are probably at
least as large as the complexation energy• Two-center scoring increments assume
transferable desolvation energies on both sides
• Is it any wonder we don’t have a global scoring function?
• Why do we accept that scoring functions are local?
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
AIM in similarity AIM in similarity searchingsearching
• Almost all classical methods are based on the bonding graph• Carbo and Hodgkin indices are an
exception
• They therefore find very similar bonding graphs• May miss similar molecules• Discriminate against scaffold hops
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
AIM in modelling: AIM in modelling: force fieldsforce fields
• We usually use all-atom models• United-atom force fields are limited and sacrifice
accuracy
• All-atom models have two major disadvantages:• They scale badly• They introduce high-frequency vibrational motion that
doesn´t interest us• Short time steps• Use SHAKE to remove (!)• Vibrational partition function plays no role in the quantities
that interest us
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
AIM in modelling:AIM in modelling:electrostaticselectrostatics
• Most force fields use point atomic multipoles• Lead to two-center terms inseparable from
dispersion/steric repulsion• Overpolarise at short distances• Are not properly shielded at long distances
• Must use fictitious and unphysical dielectric constants
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
Can we abandon AIM?Can we abandon AIM?
• Means moving to exclusively 3D methods• No comfortable solution to the
conformation problem:
2 2 2H O H O H O
Enzyme Ligand Enzyme Ligand
. . :enzyme ligand
bind desolv desolv ligand enzyligandconformatio menGG G G G
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
Can we abandon AIM?Can we abandon AIM?• We need to know where the
hydrogens are
• Which tautomer(s) are present in solution and bound to the receptor?• Requires
• Systematic tautomer searching • Very accurate pKa models
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
What do we need?What do we need?1. Fast accurate generation of
molecular surfaces• Most consistent are isodensity
surfaces• These require the electron density
(but not necessarily quantum mechanics)
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
What do we need?What do we need?2. Ways to manipulate surfaces and
surface properties quickly and efficiently
• Spherical harmonics• Critical points• Visual pattern recognition?• PC-games technology (hardware and
software)?
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
What do we need?What do we need?3. Local properties to describe
intermolecular interactions• Molecular electrostatic potential for
Coulomb-interactions
• Donor-acceptor?
• Dispersion?
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
What do we need?What do we need?4. Intermolecular energy functions
• Surface-surface overlap• Electrostatic, donor-acceptor,
dispersion, repulsion• If we include polarizability, these
can be parameterised using ab initio data
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
What do we need?What do we need?5. Anisotropic united-atom force
field• Monte-Carlo only needs energies
• Molecular dynamics needs:• MD in torsional coordinates
• Forces for anisotropic united atoms
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
What do we need?What do we need?
6. Surface-integral free energies• Critical for scoring functions, which otherwise
use the force-field intermolcular energies• Provide an attractive alternative to descriptor-
plus-interpolation QSPR-models• Solvation , lattice energies ?, vapour
pressures , partition coefficients ?, solubilities ?.....
Computer-Chemie-Centrum Universität Erlangen-Nürnberg
CompetenceCompetence• Aberdeen• Spherical-harmonic surfaces, manipulation, superposition, docking
• Erlangen• Quantum mechanics, local properties, surface-integral models,
modelling
• Oxford• Pattern-recognition
• Portsmouth• Chemometrics, mapping, conformational searching
• Southampton• Classical MD, sampling, pattern-recognition, free energies