The application of free energy calculations and molecular dynamics simulations to drug design

Nair, Pramod Chandrasekharan (2012). The application of free energy calculations and molecular dynamics simulations to drug design PhD Thesis, School of Chemistry and Molecular Biosciences, The University of Queensland.

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Author Nair, Pramod Chandrasekharan
Thesis Title The application of free energy calculations and molecular dynamics simulations to drug design
School, Centre or Institute School of Chemistry and Molecular Biosciences
Institution The University of Queensland
Publication date 2012
Thesis type PhD Thesis
Supervisor Alan E. Mark
Alpeshkumar K. Malde
Total pages 160
Total colour pages 18
Total black and white pages 142
Language eng
Subjects 0304 Medicinal and Biomolecular Chemistry
0399 Other Chemical Sciences
Abstract/Summary Drug design fundamentally involves the development of small molecules which interact with a target protein thereby altering its function. Many approaches can be used to estimate how tightly a ligand binds to a target protein. However, understanding precisely how a given ligand interacts with the target protein is often much more challenging. In particular there can be many uncertainties in regard to the placement of ligands in X-ray crystal complexes due to the limitations of the diffraction data as well as in the protocols used for structure refinement. The placement of molecules used in fragment based drug design, which are small in size (50-200Da) and often bind with low affinity to the target protein, are particularly problematic. In some cases fragments can adopt multiple stable binding modes which can be easily missed if the data is averaged and the refinement protocols assume a unique binding mode. In this thesis a combination of molecular dynamics (MD) simulation techniques and free energy calculations have been used to understand the structural and thermodynamic basis of ligand recognition in atomic detail. Specifically, the extent to which these computational techniques could be used to validate crystallographic complexes containing small fragment molecules has been examined. It is shown that MD simulations and free energy calculations could be used to correct incorrectly modeled structures and to detect cooperative binding and the formation of stable tertiary complexes that would otherwise be missed using current fragment based drug design approaches. The work demonstrated that a range of complexes could account for the density observed in crystallographic experiments. This highlighted the need for reliable and validated experimental binding and structural data to be available against which, theoretical calculations can be compared. In addition to studies of known crystal complexes the ability of high throughput free energy methods to estimate the binding affinities of a wide variety of molecules from a series of simulations using different reference states was also examined. It was shown that despite good predictions being obtained in some cases the range of molecules that could be examined was limited. A way to overcome such limitations in the case of stereoisomers is presented. Overall, this thesis demonstrates how MD simulations and free energy calculations can be used to resolve uncertainties in experimental binding affinities, binding modes, and other aspects related to X-ray refinement and computational drug design. At the same time, the work suggests novel strategies to overcome the sampling issues with the use of rapid free energy techniques in high throughput screening of diverse small molecules.
Keyword Molecular dynamics
Free energy
Thermodynamic integration
Single step perturbation
Binding mode

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Created: Fri, 11 Jan 2013, 11:38:37 EST by Pramod Nair on behalf of Scholarly Communication and Digitisation Service