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

2. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg What are molecules?

3. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg A Paradigm-shift?

4. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg 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

5. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg AIM in virtual screening and modelling Fingerprints Fragment models Similarity (usually) Topological indices and descriptors Graph theory Atomic charge models Force fields Scoring functions Generalised Born solvation models

6. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg AIM in scoring functions

7. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg Scoring 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?

8. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg AIM in similarity searching 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

9. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg AIM in modelling: force 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

10. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg AIM in modelling: electrostatics 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

11. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg Can we abandon AIM? Means moving to exclusively 3D methods No comfortable solution to the conformation problem:

12. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg 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 pK a models 

13. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg 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)

14. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg 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)?

15. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg What do we need? 3.Local properties to describe intermolecular interactions Molecular electrostatic potential for Coulomb-interactions Donor-acceptor? Dispersion?

16. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg 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

17. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg 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

18. Computer-Chemie-CentrumUniversität Erlangen-Nürnberg 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 ?.....

19. Computer-Chemie-CentrumUniversität Erlangen-NürnbergCompetence 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