1 / 19

Virtual screening and modelling: must it be atoms?

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?. A Paradigm-shift?. Atoms in molecules (AIM).

jermaine-alford
Download Presentation

Virtual screening and modelling: must it be atoms?

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

  2. What are molecules?

  3. A Paradigm-shift?

  4. 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. 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. AIM in scoring functions

  7. 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. 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. 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. 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. Can we abandon AIM? • Means moving to exclusively 3D methods • No comfortable solution to the conformation problem:

  12. 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 

  13. What do we need? • Fast accurate generation of molecular surfaces • Most consistent are isodensity surfaces • These require the electron density (but not necessarily quantum mechanics)

  14. What do we need? • Ways to manipulate surfaces and surface properties quickly and efficiently • Spherical harmonics • Critical points • Visual pattern recognition? • PC-games technology (hardware and software)?

  15. What do we need? • Local properties to describe intermolecular interactions • Molecular electrostatic potential for Coulomb-interactions • Donor-acceptor? • Dispersion?

  16. What do we need? • Intermolecular energy functions • Surface-surface overlap • Electrostatic, donor-acceptor, dispersion, repulsion • If we include polarizability, these can be parameterised using ab initio data

  17. What do we need? • Anisotropic united-atom force field • Monte-Carlo only needs energies • Molecular dynamics needs: • MD in torsional coordinates • Forces for anisotropic united atoms

  18. What do we need? • 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. Competence • 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

More Related