Molecular Modelling for Medicinal Chemistry (F13MMM) Room A36

Transcription

1 Molecular Modelling for Medicinal Chemistry (F13MMM) Room A36 Assisted reading Molecular Modelling: Principles and Applications. Andrew R. Leach. Prentice Hall, 2 nd edition, 2001 Workshop questions student participation Examination Aim: appreciate some of the theoretical and conceptual background to molecular modelling 1

2 Overview Conceptual background No quantum chemistry Empirical Force Fields Molecular dynamics (MD), Monte Carlo, conformational searching Docking Cheminformatics Pharmacophores, Similarity, Descriptors, quantitative structure activity relationship (QSAR) Chemistry Computational Chemistry 2

3 What is Molecular Modelling? Ab initio quantum chemistry HF, DFT, MP2, CCSD(T) Semi-empirical Classical/force field based methods Molecular Dynamics simulations Docking Cheminformatics Bioinformatics What can Molecular Modelling tell us? Molecular structure Bond length < 0.1Å, bond/torsion angle < 1 Spectroscopy UV, IR, NMR, Energetics cis vs trans Thermodynamics Binding, reaction enthalpy < 5 kcal/mol Dynamics 3

4 Evolution Jonathan Hirst Biomolecular modelling Ligand binding spectroscopy Lattice models chemoinformatics bioinformatics Molecular Dynamics ab initio folding 4

5 Richard Wheatley Non-covalent bonds Molecular Simulations % of bond energy 100 Uncertainty in the best calculations The orbital approximation Structures and spectra of floppy molecules (such as H 2 O-Ar) 0 Covalent Van der Waals H 2 -H 2 O, N 2 -H 2 O, O 2 -H 2 O, CO-H 2 O: Small organic molecules Quantum Chemistry Nick Besley Use of computers to study the structure and spectroscopy of molecules For example: New methods to solve the Schrodinger equation Electronic spectroscopy of molecules in solution and on surfaces NMR of defects in fullerenes and nanotubes 5

6 Computational Nanoscience Elena Bichoutskaia like-charged dielectric particles can be strongly attracted! Implications/Applications formation of stable colloidal suspensions transportation of pharmaceutical powders protein interactions self-assembly of macro-anions formations of clouds and stars David Robinson Membrane simulations and spectroscopy Condensed phase spectroscopy: insights from quantum chemistry Explicit molecular environment quantitative optical spectroscopy Design novel fluorophores e.g. 5-hydroxyindole (1000x smaller than GFP): probe function/dynamics of proteins & membranes 6

7 Overview Recognise the extent to which molecular modelling can interpret and predict complex chemical/biological activity. Modelling in drug design/development Statistical methods: chemical structure activity Every attempt to employ mathematical methods in the study of chemical questions must be considered profoundly irrational and contrary to the spirit of chemistry. If mathematical analysis should ever hold a prominent place in chemistry - an aberration which is happily almost impossible - it would occasion a rapid and widespread degeneration of that science. Auguste Comte, Cours de philosophie positive,

8 Drug discovery today the use of computers and computational methods permeates all aspects of drug discovery today Structure drawing Database entry-management-query 2D to 3D structure conversion Molecular visualization QM, MM, MD, conformational searching Biomolecular structure refinement Types of Molecular Models Wish to model molecular structure, properties and reactivity Range from simple qualitative descriptions to accurate, quantitative results Costs range from trivial to months of supercomputer time Some compromises necessary between cost and accuracy of modelling methods 8

9 Plastic molecular models Fixed bond lengths and coordination geometries Good enough for qualitative modelling of the structure of some molecules Easy and cheap Provide a good feeling for the 3D structure of molecules No information on properties, energetics or reactivity Potential Energy Surfaces Central concept PES structure, energetics, properties, reactivity, spectra and dynamics PES cannot be obtained from experiment Except in very simple cases Need efficient and accurate methods 9

10 Equilibrium molecular structures correspond to the positions of the minima Energetics of reactions can be calculated from the energies or altitudes of the minima for reactants and products A reaction path connects reactants and products through a mountain pass A transition structure (TS) is the highest point on the lowest energy path Reaction rates from the height and profile of the PES around the TS Shape of the valley around a minimum vibrational spectrum Each electronic state of a molecule has a separate PES; separation between these surfaces yields the electronic spectrum Dipole moment, polarizability, NMR shielding, etc. depend on the response of the energy to applied electric / magnetic fields 10

11 Internal coordinates (Z-matrix) Cartesian Easily obtained from modelling software Often software will automatically generate internal coordinates for optimisation Z-matrix Build geometry from known bond lengths, angles, etc. Can optimise a selected subset of internal coordinates 11

12 Worksheet 1 Answer the following questions, based on your reading of Chapter 1 of Leach s Principles of Molecular Modelling. Directions to the relevant sections are given in square brackets; page numbers refer to the 2 nd edition. Copies of the book should be available in the library. Please hand your work in (date stamped) at the Student Support Office by Tuesday 16 th October, 3:00 pm. This is part of the assessed coursework associated with the module. You must be prepared to present your answer at the next timetabled session of the module. 12