Husby, J; (2013) In silico studies of nucleic acid complexes with proteins, and therapeutic small molecules. Doctoral thesis , UCL (University College London).

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Abstract

In silico approaches to nucleic acid targeted drug discovery have been used in order to study duplex DNA, in complexes with proteins as well as more unusual form of G-rich DNA folded into higher-order structures termed as G-quadruplexes, in complexes with therapeutic small molecules. The overall aim of this work has been to provide insight into the stability, recognition, energetics of binding and dynamic behavior of these DNAs in complexes with the STAT3βtc homodimer:DNA complex and with therapeutic small molecules in G-quadruplex/pyridostatin and G-quadruplex/fragment complexes by means of combined in silico approaches. The techniques of explicit solvent molecular dynamics (MD) simulations, and subsequent calculations of the free energies of binding, molecular docking, and 3D-pharmacophore modeling have been applied to study STAT3 and G-quadruplex DNA, promising targets for anticancer therapeutic intervention. Analysis of the data obtained from multiple 50-ns MD simulations of the STAT3-DNA complexes has suggested how the transcription factor STAT3 interacts with duplex DNA, the nature of the conformational changes, and ways in which func- tion may be affected. A majority of known pathologic mutations affecting the DNA-biding region of the STAT3 have been found at the protein-DNA interface, and they have been mapped in detail. The STAT3 conformations obtained from these MD simulations have been subsequently used as a basis for a comparative multiple-target molecular docking study with an in-house library of potential STAT3 inhibitors, providing a rational of their binding in the absence of structural data. A novel “dynamic docking” approach (robust platform of numerous MD simulations) has been developed to address the G-quadruplex receptor and ligand flexibility issue, and subsequent conformational change upon binding. The strength of binding at different regions and both sites of the G-quadruplex were then closely examined. An in silico study of a fragment-based approach towards G-quadruplex stabilizing ligands has also been explored, in parallel with experimental studies, to assess whether this could provide a reliable rapid approach to finding hit fragments in the case of the c-MYC promoter quadruplex.

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