Computer-Chemie-CentrumUniversität Erlangen-Nürnberg Virtual screening and modelling: must it be atoms? Tim Clark Computer-Chemie-Centrum Universität Erlangen-Nürnberg.

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


What are molecules?What are molecules?

C

H

O

H

H

H


A Paradigm-shift?A Paradigm-shift?


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


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


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

bind desolv desolv ligand enzymeG G G G


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?


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


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


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


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

bind desolv desolv ligand enzyligandconformatio menGG G G G


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


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)


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)?


What do we need?What do we need?3. Local properties to describe

intermolecular interactions• Molecular electrostatic potential for

Coulomb-interactions

• Donor-acceptor?

• Dispersion?


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


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


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 ?.....


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

Computer-Chemie-CentrumUniversität Erlangen-Nürnberg Virtual screening and modelling: must it be atoms? Tim Clark Computer-Chemie-Centrum Universität Erlangen-Nürnberg.

Documents

tim clark computerchemie

richard bader slide

quantum mechanics slide

solvation models

accuracy allatom models

similar molecules

global scoring function

short distances