Molecular Modelling and Structure-Based Drug Design

Course provider:
The University of Leeds

Course contact:
Brian P. Clark (bmbbpc@bmb.leeds.ac.uk)

Summary:
The aim of this module is to use practical modelling activities to introduce the basic principles and applications of molecular modelling, and to show how modelling can be used for de novo structure-based drug design.

Syllabus:

1. Molecular Mechanics
a. The molecular potential energy function
b. The empirical force field
c. Sources of force field data
d. Some examples of important force fields
2. Energy Minimisation
a. First derivative techniques: steepest descent and conjugate gradients
b. Second derivative techniques: Hessian matrix and Newton-Raphson
c. Global optimisation (simulated annealing, Tabu search, genetic algorithms)
3. Molecular Dynamics and Monte Carlo Simulations
a. Brief introduction to statistical mechanics
b. Molecular dynamics simulations
c. Monte Carlo simulations
4. Conformational Analysis
a. Systematic methods
b. Random search methods
c. Distance geometry
d. Molecular dynamics
5. Solvation
a. Brief comparison of different solvation methods
b. Periodic boundary conditions
6. Calculation of Thermodynamics Parameters
a. Difficulties with thermodynamics calculations
b. Free energy perturbation method
7. Structure-Based Drug Design
a. Predicting protein-biomolecule structures
b. The search problem
i. Constraint-based methods – DOCK algorithm
ii. Complete search of conformational space – Fourier transform method
c. Virtual screening
d. Conformational flexibility
i. Stochastic search methods
ii. Combinatorial search methods

Further details:

The ability to write simple programs in Java (or C, C++) is necessary for this module.

The assessment elements:

for each section of the course there will be one tutorial exercise which must be completed satisfactorily;

there will be three written assessments.

Assessment weightings

Your final grading for the module will be a weighted mean of the marks for your written assessments.

Assessment 1. Simulated Annealing, 30%
Assessment 2. Molecular Simulation, 30%
Assessment 3. Structure-Based Drug Design, 40%

Technical requirements:
Windows 9X/NT/2000/XP (The specialist software used in this module is not compatible with Windows ME), Microsoft Internet Explorer 6, with Sun Java Plugin 1.4.2. or higher.

References:
Andrew R. Leach, Molecular Modelling, Principles and Applications, 2nd Edition, Pearson, Prentice Hall, 2001.
M.P. Allen and D.J. Tildesley, Computer Simulation of Liquids, Oxford Science Publications, 1987.

U. Burkert and N.L. Allinger, Molecular Mechanics, ACS Monograph 177. Washington D.C., American Chemical Society, 1982.

J.A. McCammon and S.C. Harvey, Dynamics of Proteins and Nucleic Acids, Cambridge University Press, 1987.

Course provider:	The University of Leeds
Course contact:	Brian P. Clark (bmbbpc@bmb.leeds.ac.uk)
Summary:	The aim of this module is to use practical modelling activities to introduce the basic principles and applications of molecular modelling, and to show how modelling can be used for de novo structure-based drug design.
Syllabus:	1. Molecular Mechanics a. The molecular potential energy function b. The empirical force field c. Sources of force field data d. Some examples of important force fields 2. Energy Minimisation a. First derivative techniques: steepest descent and conjugate gradients b. Second derivative techniques: Hessian matrix and Newton-Raphson c. Global optimisation (simulated annealing, Tabu search, genetic algorithms) 3. Molecular Dynamics and Monte Carlo Simulations a. Brief introduction to statistical mechanics b. Molecular dynamics simulations c. Monte Carlo simulations 4. Conformational Analysis a. Systematic methods b. Random search methods c. Distance geometry d. Molecular dynamics 5. Solvation a. Brief comparison of different solvation methods b. Periodic boundary conditions 6. Calculation of Thermodynamics Parameters a. Difficulties with thermodynamics calculations b. Free energy perturbation method 7. Structure-Based Drug Design a. Predicting protein-biomolecule structures b. The search problem i. Constraint-based methods – DOCK algorithm ii. Complete search of conformational space – Fourier transform method c. Virtual screening d. Conformational flexibility i. Stochastic search methods ii. Combinatorial search methods
Further details:	The ability to write simple programs in Java (or C, C++) is necessary for this module. The assessment elements: for each section of the course there will be one tutorial exercise which must be completed satisfactorily; there will be three written assessments. Assessment weightings Your final grading for the module will be a weighted mean of the marks for your written assessments. Assessment 1. Simulated Annealing, 30% Assessment 2. Molecular Simulation, 30% Assessment 3. Structure-Based Drug Design, 40%
Technical requirements:	Windows 9X/NT/2000/XP (The specialist software used in this module is not compatible with Windows ME), Microsoft Internet Explorer 6, with Sun Java Plugin 1.4.2. or higher.
References:	Andrew R. Leach, Molecular Modelling, Principles and Applications, 2nd Edition, Pearson, Prentice Hall, 2001. M.P. Allen and D.J. Tildesley, Computer Simulation of Liquids, Oxford Science Publications, 1987. U. Burkert and N.L. Allinger, Molecular Mechanics, ACS Monograph 177. Washington D.C., American Chemical Society, 1982. J.A. McCammon and S.C. Harvey, Dynamics of Proteins and Nucleic Acids, Cambridge University Press, 1987.

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Updated 2 July 2009 by Heather Vincent