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Title: Computation of hydrogen bond basicity as a descriptor in bioisosterism : a quantum chemical topology perspective
Author: Green, Anthony James
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2013
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Hydrogen bonding is a regularly occurring non covalent interaction in biological systems. Hydrogen bonding can influence a drug’s interaction with its target. It is therefore important to practically measure the relative strengths of hydrogen bonds. Hydrogen bond basicity is a measure of a hydrogen bond acceptor’s capacity to accept hydrogen bonds. There are many hydrogen bond basicity scales. However, the pKBHX scale is claimed to be the most relevant to medicinal chemists because it gives a thermodynamically deducible values for each site in polyfunctional bases. A computed property, the change in energy of the hydrogen bond donor hydrogen bond atom ΔE(H), derived from the quantum theory of atoms in molecules has been found to correlate strongly with pKBHX values for OH and NH hydrogen bond donors. In particular, R2 values of 0.95 and 0.97 have been found when methanol and methylamine respectively are used as hydrogen bond donors. The property ΔE(H) has also been successfully used to predict the pKBHX values of an external data set and the values of polyfunctional bases. The strength of the correlations are not dramatically affected by using scaled down fragments of bases, or by relaxing the convergence criteria during the geometry optimisation step of calculations. The relationship between ΔE(H) and pKBHX has been found to break down for tertiary amines, and more generally for strong proton acceptors with pKBH+ values greater than 6. The successful pKBHX prediction model was, however, unsuccessful in predicting drug binding data and pKBHX values of bases that accept two separate hydrogen bonds. At this moment in time both the reason why the relationship between pKBHX and ΔE(H) is present and then breaks down for strong proton acceptors is unfortunately unknown.
Supervisor: Popelier, Paul Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available