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Title: Towards ligand design : Quantum Chemical Topology descriptors of heterocyclic compounds and pKa prediction from ab initio bond lengths
Author: Griffiths, Mark
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2013
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Bioisosterism is a field that is widely applied to biological molecules, including drugs and agrochemicals. Bioisosterism is the replacement of an active fragment in a molecule with another fragment similar in activity. The replacement is designed to alter the behavior of the molecule in its target environment. In previous work a bioisostere database called the Quantum Isostere Database (QID) was built out of descriptors derived from the theory of Quantum Chemical Topology (QCT). The current work aims to expand the existing QID to include ring fragments. A series of rings were characterised by QCT properties taken from the ring. It was found that four features of a ring each independently have a systematic effect on the ring’s properties. In other words, each of the characteristics of a ring can be changed and have the same effect on the ring’s properties irrespective of the other ring features. The rings were also characterised using the three QCT properties taken from a point within the ring. The three properties established a space where rings were positioned based on their respective three properties. The positions of the rings showed that the space was able to discern between ring types, and that the features of a ring could be predicted if only its three properties were known. To improve the QID the alignment method and scoring were tested. The alignment procedure is unable to correctly align collinear fragments. Therefore, a principal axis alignment procedure was successfully employed to align collinear fragments. For terminal fragments an alternative alignment procedure was proposed to account for the increased rotational freedom. A global axis system meant that the direction dependent properties for all fragments were expressed in this new axis system. This idea was extended further and it was found that the geometry of a molecule was imprinted in the electrostatics when they were expressed in the global axis system. Finally, a pKa prediction method which correlates a single ab initio bond length was tested against two data sets (enols and guanidines). The method relies on subsets to form, where molecules within a subset share a chemical or structural commonality. These subsets were able to distinguish between the five tautomeric forms for the guanidines and different conformations for the enols. All predictions were within 1.0 pKa units of experimental values.
Supervisor: Popelier, Paul Sponsor: Not available
Qualification Name: Thesis (Eng.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: pKa prediction ; Ligand Design ; Quantum chemical topology ; heterocyclic rings