Structure-Function Relationship

1. Molecular modelling in rational
drug design
Rodrick S. Katete
Lecturer: Prof. H. Dirr
Let’s make a man in our image

2. Outline
• Uses of molecular models
• Generation of 3D molecular structures
• Ligand modelling
• Protein modelling
• Quality in protein models
• Computational tools for geometry optimisation
• Conformational analysis
• Determination of molecular interaction potential
• 2D QSAR methods
• 3D QSAR methods
• Molecular modeling of influenza neuraminidase
inhibitors

3. The aim of molecular modelling
in ration drug design
• To support structural biochemists to make "better"
compounds in order to speed up the drug discovery
process
“ A model must be wrong, in some respects, else it will
be the thing itself. The trick is to see where it is
right.”
“It has not escaped our notice that the specific pairing
we have postulated immediately suggests a possible
copying mechanism for the genetic material.”
amino acid seq.
folding JNK1

4. Uses of molecular models
• To simplify a complex structure or process
• Didactical illustration
• Visualise molecules
• Study the structure and properties of a molecule
• Study molecular interaction and reaction mechanisms
• Compare the structure and properties of molecules
• Predict the protein-ligand interactions
• Predict the properties of molecules
• Predict reaction mechanisms

5. Generation of 3D molecular structures
• Use X-ray, Neutron diffraction and NMR data bases
• Fragment libraries with standard geometries
• Sketch and covert to 3D
• Conversion of 2D structural data into 3D form
(CORINA & CONCORD)

6. Ligand modelling
• Structure generation
• Molecular mechanics/dynamics (MM/MD)
• Quantum mechanics (QM)
• Conformational analysis
• Calculation of physicochemical properties
• Comparison of molecules

7. Protein modelling
• Sequence comparison
• Homology modelling
• Simulation of protein folding
• Protein dynamics

8. Quality in protein models
• Stereochemical accuracy
• Packing quality
• Folding reliability

9. Stereochemical accuracy
• Torsion angles: Mainchain torsion
Sidechain torsion
• Planarity of peptide bonds
• Chirality of Cα-atoms
• Bond lengths
• Bond angles
• Planarity
Proteins Struct. Func. Gen. Vol. 12, 345-364 (1992)

10. Packing quality
• Interaction distances
• Secondary structural elements
• Hydrophobicity
• Solvent accessible surface of amino acids
• Unsatisfied buried H-bond
donors/acceptors

11. Folding reliability
3D-comparison modes/template structure
 RMS deviations between backbone atoms
3D-1D-profiles
 Comparison of environmental strings with amino acid
sequences
Knowledge-based potentials
 Energy-based comparison

12. Computational tools for geometry
optimization (Steric complementarity)
• Force fields (molecular mechanics)
ETOTAL = ES + EB + ES-B + E T + EvdW + EDP-DP + Eoop
• Energy-minimisation procedures
• Use of charge, solvent effects
• Quantum mechanics methods
• Ab initio methods
The NIH Guide to Molecular Modelling

13. Conformational analysis
• Conformational analysis using systematic search
procedures
• Conformational analysis using Monte Carlo methods
• Conformational analysis using molecular dynamics
Conformational strains
• Steric strain
• Angle strain
• Van der Waals strain
• Torsional strain
• Torsional angle
• Ring strain

14. Determination of molecular interaction
potential (Electrostatic complementarity)
• Molecular electrostatic potentials (MEPs)
• Methods of calculating atomic point charges
• Topological charges
• Quantum mechanics
• Methods of generating MEPs
• Visualisation of MEPs
• Molecular interaction fields
• Hydrophobic interaction
• Display of properties on a molecular surface
Molecular Interaction field
Van der Waals radius
Effective number of electrons
Polarisability
Electrostatic charge
Optional hydrogen bonding
Hydrogen bonding radius
Number of hydrogen bond donated
Number of hydrogen bond accepted
Hydrogen bonding type

15. 2D-QSAR
• Application of multiple linear regression techniques
for quantitative relationships
• topological and electrotopological state (E-state)
descriptors
2D-QSAR descriptors
• Size-related
• Hydrophobicity-related
• Electronic effects
• Hydrogen bonding descriptors
• Topological descriptors

16. 3D QSAR methods
3D-QSAR (Three-Dimensional Quantitative Structure- Activity
Relationships)
Chemistry Dogma: one chemical–one structure–one
parameter value
Chemical properties & biological behaviour have to do with
chemical structure
Statistical correlation between biological activity to three-
dimensional electronic and steric properties
3D Structure and distribution of dispersion, electrostatic,
hydrophobic, H-bonds and pharmacophoric patterns
Chemical interactions are three-dimensional (3D) events

17. The CoMFA (Comparative Molecular
Field Analysis) method
• Can superimpose conformers based on Molecular
Interaction Fields (MIFs) to find biologically-active
properties
• Depends on ligand conformation
• Depends on molecular alignments
– atom-by-atom pairwise RMSD fit
– fit of molecular interaction fields and associated
properties
– fit of molecular surfaces
• Depends on parameters describing Interaction Fields
• Doesn't explicitly account for hydrogen bonds

18. CoMFA related methods
• CoMSIA
• GRID and GOLPE

19. Molecular modeling of influenza
neuraminidase inhibitor
Structure, Vol. 5 (9): 1139-1145. 1997.

20. Molecular modeling of influenza
neuraminidase inhibitor

21. Molecular modeling of influenza
neuraminidase inhibitor

23. Molecular modeling of influenza
neuraminidase inhibitor
Structure, Vol. 5 (9): 1139-1145. 1997.

24. “However, it is dangerous, or at least
meaningless, to draw conclusions that cannot
be tested experimentally. Thus, any prediction
based on extrapolation beyond the range of
experimental evidence is of doubtful validity,
until the range of observation can be extended
to test it.”
Carole R. Gatz

25. References
Book
• Holtje, H. D., Sippl, W., Rognan, G. and Folkers (2003). Molecular modeling.
Basic principles and applications (2nd Ed.) WILEY-VCH GmbH & Co. KGaA,
Weinheim, Germany. Pp 1-214. (BIOPHY, QP 517.M3 MOL)
Journal sources
• Meyer, E. F., Swanson, S. M. and Williams, J. A. (2000). Molecular modelling and
drug design. Pharmacology and Therapeutics, 85, 113-121.
• Wieman, H., Tondel, K., Anderssen, E. and Drablos, F. (2004). Homology-based
modelling of targets for rational drug design. Mini-review in Medical Chemistry, 4,
793-804.
• Mezey, P. G. (2000). Computer aided drug design: Some fundamental aspects.
Journal of molecular modeling, 6, 150-157.
• Oprea, I. T. (2002). On the information content of 2D and 3D descriptors for
QSAR. Journal of Brazilian Chemical Society, 13 (6), 811-815.

26. References (cont.)
• Goodford, P. D. (1984). A computational procedure for determining energetically
favorable binding sites on the biologically important macromolecules. Journal of
Medicinal chemistry, 28 (7), 849-857.
• Wade, R. C., Henrich, S. and Wang, T. (2004). Using 3D protein structure to derive
3D-QSARs. Drug Discovery Today: Technologies, 1 (3), 241-246.
• Bonnet, P. and Bryace, R. A. (2004). Molecular dynamics and free energy analysis
of neuraminidase–ligand interactions. Protein Science, 13, 946-957.
• Friesner, R. A. (2005). Ab initio quantum chemistry: Methodology and applications.
PNAS, 102 (19), 6648-6653.
• Weiner, P. K., Langridge, R., Blaney, J. M., Schaefer, R. and Kollman, P. A. (1982).
Electrostatic potential molecular surfaces. Proc. Natl. Acad. Sci. USA., 79, 3754-
3758.
• Mulholland, A. J. (2005). Modelling enzyme reaction mechanisms, specificity and
catalysis. Drug Discovery Today, 10, 1393-1402.

27. References (cont.)
Wade, R. C. (1997). ‘Flu’ and structure-based drug design. Structure, 5 (9),
1139-1145.
Electronic sources
http://www.chem.swin.edu.au/modules/mod2/startp.html Last updated on :
08/08/2006 11:10:42 (Data for Molecular Modelling)
http://molvis.sdsc.edu/protexpl/homolmod.htm Eric Martz, June 2001
(Comparative ("Homology") Modeling)
http://projects.villa-bosch.de/mcm/projects/uppsala/lectures/lecture1
(‘Flu’ and structure-based drug design)