Computer aided drug design: Basic concepts. Computational chemistry: Molecular modelling Chemoinformatics

Transcription

1 Computer aided drug design: Basic concepts The objective is to suggest new molecules that can be synthesised or purchased and tested for a desired property, using all available information (and computers). Computational chemistry: Molecular modelling Chemoinformatics

2 Design of molecules with improved properties Properties: Pharmacodynamic (the study of the biochemical and physiological effects of drugs and the mechanisms of drug action and the relationship between drug concentration and effect) Biological effect Biological activity (of a specific receptor/protein) Pharmacokinetic (the study of how a body absorbs, distributes, metabolizes and excretes drugs) Metabolism Distribution alf life Membrane permeability

3 What makes a compound a good inhibitor? Protein ligand interactions Ionic interactions ydrogen bonds Dipole-dipole moment Interactions with metals van der Waal interactions Sovatisation/desolvatisation Binding entropy loss of conformational flexibility

4 Sovatisation/desolvatisation + N 3 + Ki Biological process + N 3 + important for binding difficult to estimate

5 Ligand conformations and binding entropy Binding entropy the energy cost that is due to the loss conformational flexibility due to binding to the protein. Bioactive conformation the ligand conformation that is bound to the protein Global minimum the conformation in solution giving the lowest energy conformation

6 Chemical information Proteins mainly the active site Ligands the chemical structure Physicochemical properties, e.g. Lipophilicity, - bond donating capabilities Structural descriptors For visualisation Conformational analysis, investigation of the flexibility of the chemical structure

7 ow to compute important porperties? A. 2D calculations B. Quantum chemistry C. Molecular mechanics A. Based on 2D description of the chemical structure. structural descriptors From the 2D graph, e.g. Connectivity, MW, -bond donors, No of rotable bonds From models based on the 2D structure, e.g. logp, polar surface area Weight a_nn 2 a_n 11 TPSA 196.1

8 B. Quantum chemistry. Calculate energies based on movements of electrons (wavefunctions) and the Schrödinger equation. ab initio: No parameters needed. The calculation uses a so called basis set of functions that can be set by the user. Semi-empirical: Uses parameters determined by experimental data and ab initio to simplify the equations. These methods can be used for both conformational analysis and for calculation of physicochemical properties. Takes long time only on few molecules/atoms

9 C. Molecular mechanics. Uses force fields to compute energies. Based on classic physics and define atom and bonds as ball and springs. Need parameters generated from ab initio calculations for every atom and bond types. stretching bending rotation δ+ spatial δ charge Both conformational analysis (usually very good) and for calculation of physicochemical properties (mainly for visualisation).

10 The use of physico-chemical properties and conformational analysis Diversity analysis SAR and QSAR Pharmacophore modelling Structure based design

11 Get the molecules into the computer File format: contain information about atoms and their position to each other. These files are readable (and editable) in a text editor 2D 3D Atom types: contain information about properties about certain types of atoms, e.g. amide N vs. amine N. Necessary for molecular mechanic calculations and also for certain file formats where bond information is not stored (the atom type information is used to draw the correct bond types) In general very few rules and guidlines for file format and atom types. Different programs uses the same extention but gives different result

12 Proteins 3D model: X-ray crystallography and Nuclear Magnetic Resonance (NMR) Crystalisation and X-ray Gives information about heavy atoms position in 3D (i.e. no ). Can not distinguish between N and (and in some cases C). Crystallographer s model the protein based on the atomic positions. The information is stored in a pdb -file Most solved models are deposited into Protein Data Bank ( Today > structures

13 Softwares Drawing programs (Isis, ChemDraw) File convertion (Babel) 2D -> 3D (Concord, Corina) 2D and 3D descriptor calculations (Dragon, Moe) Molecular mechanics (Maestro, Moe, Sybyl) Quantum chemistry (Spartan, Gaussian) Visualisation (Sybyl, Rasmol, Chime, Pymol)

14 Workstations ardwares Platforms (specific computer hardware): SGI, Sun, P, IBM perative systems (The low-level software which handles the interface to peripheral hardware): Irix, Sun Solaris, Sun S, Personal Computers Platforms: Apple Computer's, IBM PC compatible perative systems: Mac S, Microsoft Windows, Linux (Linux-Redat, Linux-SuSE, Fedora)

15 Summary basic concept in CADD Want to compute properties regarding protein-ligand interactions, e.g. electrostatic interactions, -bonding capacity, van der waal interactions, solvatisation effects, and binding entropy. Physicochemical propterties and conformational analysis yield information for structural descriptors and visualisation. Can do it by Quantum chemistry (e - -movments, takes long time) or Molecular mechanics (classic physics, faster). Structural descriptors can also be calculated from 2D sketch. 3D coordinates for ligands can be obtained by 2D to 3D conversion programs. 3D coordinates for proteins are obtained from X-ray crystallography or NMR In molecular mechanics and in visualisation the atom types (and bond type) need to be defined and parameterised File formats for molecular representation have not a define rules or guidelines. Usually a text-file that can be read (and edit) in a text editor.