Conformational Studies on Some Inhibitors of Thermolysin and EC

Forrest, Fiona Ruth Ferguson (1987) Conformational Studies on Some Inhibitors of Thermolysin and EC PhD thesis, University of Glasgow.

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Molecular modeling is an exciting new approach in the field of drug design. A molecule's activity as a drug is dependent upon its conformation i.e. the three dimensional arrangement of its functional groups. Molecular mechanics coupled with interactive computer graphics is an excellent technique for studying the conformations of small molecules and this thesis presents a discussion of this technique and its application to some inhibitors of the enzymes Thermolysin and EC 3.4. 24.11. An introduction to the role of molecular mechanics in computer assisted drug design is given in Chapter One. Chapter Two describes the calculation of steric energies and the potential functions used to do this, while the procedures used for conformation generation and energy minimisation are discussed in Chapter Three (Appendix A lists one of the programs used for the conformation generation). The MOL software package is an interactive modeling system for small molecules which has been developed at Glasgow and Chapter Four contains a description of this system and its options. The structure and function of many enzymes is of prime importance in drug design since drugs often act by inhibition of enzymic pathways. Since very few enzyme structures are known from X-ray crystallography the primary source of information is enzyme kinetics and Chapter Five discusses some important properties of enzymes, such as their functions as catalysts, substrate and inhibitor kinetics and evolutionary pathways. EC (a mammalian enzyme) and Thermolysin (EC, a bacterial enzyme) have very similar substrate specificities and are inhibited at comparable rates by several inhibitors. Very little is known about the active site of EC , however, the structure of Thermolysin is well known from X-ray crystallography and in Chapter Six the known features of active sites of both enzymes are discussed and compared. It is known that two isosteric inhibitors of Thermolysin, B-Phenylpropionyl-L-Phe and Carbobenzyoxy-L-Phe, bind in completely opposite orientations. This unexpected phenomenancan be explained by conformational studies on the two inhibitors. In both cases the enzyme does not bind the lowest energy conformer, however in each case it binds the conformer which has both low energy and gives a good fit to the active site. The results of conformational studies of inhibitors of EC are also discussed in Chapter Six and comparison of the low energy conformers with inhibitors of Thermolysin (from X-ray data) point to differences in the positions and sizes of the S1 and S2' subsites of the two enzymes. Both enzymes are highly specific for hydrophobic groups in the S1' site, with Phe being the most favoured residue. From the X-ray studies of Thermolysin it is known that the Phe side chain is bound with torsion angles of roughly 170 and 80. It is interesting to note that these torsion angle values are very common in many of the low energy conformers and it seems reasonable to assume that the high level of specificity arises from the fact that the side chain of the Phe, Leu etc. are normally in the most favourable position for binding to the S1 hydrophobic pocket without rearrangement. Several other differences between the two enzymes lead to the conclusion that their functional similarity is more likely to be a product of evolutionary convergence on function than of divergence from a common ancestor. Chapter Seven contains a brief summary of the programming which was done during the course of this project paying particular attention to both the motivation and methods involved in programming an array processor and as previously mentioned Appendix A contains a listing of the GLOMIN program - a conformation generation program which was modified to run on an array processor during the course of this project. Finally, Chapter Eight contains a discussion of work carried out in conjunction with Professor A. Y. Meyer while he was on sabbatical leave at Glasgow University. This work shows that force fields can be modified quite simply to give more transferable non-bonding parameters by the inclusion of an electrostatic term. A paper on this work has been published in the Journal of Computational Chemistry and a copy of this paper is given in Appendix B.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry, Pharmacology
Date of Award: 1987
Depositing User: Enlighten Team
Unique ID: glathesis:1987-77560
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 09:05
Last Modified: 14 Jan 2020 09:05

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