City Research Online

Abstract

Two types of study on drugs and drug receptors are covered in this work, (1) where the molecular structure of the receptor is unknown and (2) where molecular coordinates are known for the receptor. For the first the neurotransmitter amino butyric acid (GABA) was examined. The GABA molecule is particularly troublesome because it is difficult to deal theoretically with a polar molecule in a polar solvent (aqueous - a commonly used approximation to the biophase), and GABA has too many internal rotations for accurate experimental treatment. We have, however, established using variable-temperature NMR that no particular conformational preferences exist for GABA in solution, without having to resort to any assumptions on the angles of the minima or their associated coupling constants. Of the theoretical methods for determining solution conformation, a 'continuum' model shows GABA to be essentially rigid, and a 'discrete' model gives several low-energy minima for GABA. We discuss these results and the problems associated with each method, and with a hybrid of the two methods. Gas-phase theoretical methods have also been examined. We found that reliable geometries and conformational energies can be obtained, provided allowance is made for the known shortcomings of each method.

For the competitive GABA antagonist bicuculline (BIC) we have used a novel NMR method, involving the observed temperature-dependence of BIC coupling constants and chemical shifts, to show that 3 low- energy conformations are present in solution with low barriers between them. The addition of an extra N-methyl group or proton to BIC, however, increases the hindrance to rotation so that only one minimum was observed by NMR in solution. From a knowledge of the accuracy of the NMR measurements we estimated a lower bound for the energy of the next minimum above the global minimum. This estimate was then used to show that the conformer observed for both N-methyl and protonated BIC in solution is the active conformation.

Previous comparisons between GABA and GABA agonists and antagonists are given, in which no distinction is made between agonist and antagonist structural requirements for activity. In the light of all our NMR results our own comparisons were then made from which separate requirements have been deduced.

For the second type of study, where receptor coordinates are known, we have developed an extensive molecular graphics system (IM-DAC) for examining active-site clefts of receptors and the docking of drug molecules into receptors - with routines for examining in detail the space available for molecular modification and for intermolecular energy minimisation.

We have used a known receptor structure (thermolysin), as a model for a similar receptor of unknown molecular structure (enkaphalinase), and have used IMDAC to model novel enkaphalinase inhibitors based on existing thermolysin inhibitors. In addition, a novel possible mode of binding for an enkaphalinase inhibitor has been determined.

Publication Type:	Thesis (Doctoral)
Subjects:	Q Science > QC Physics Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology
Departments:	School of Science & Technology > School of Science & Technology Doctoral Theses Doctoral Theses

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