The design of bacterial inhibitors modelled on growth factors
H. N. Rydon · Proceedings of the Royal Society B Biological Sciences · 1949
Abstract Fildes, in 1940, put forward a plea for ‘A rational approach to research in chemotherapy’ in which he advocated research directed towards the preparation of modified essential metabolites which should be sufficiently closely related to the essential metabolite on which they were based as to fit the same enzyme, but sufficiently dissimilar as to be themselves devoid of essential metabolic activity. This idea was taken up widely, and fruitfully, but often without due regard to the factors making for true similarity between metabolite and inhibitor; the present paper is an appeal for such a rational approach to chemotherapy to be based on a proper appreciation of the structural factors on which such similarity must be founded. It must be admitted that most of the metabolite analogues which have been prepared and tested as a result of the general acceptance of Fildes’s idea have proved of little value as practical chemotherapeutic agents. A possible reason for this lack of success lies in the fact that the analogies between metabolite and inhibitor have been purely ‘pictorial’ in nature; in general, the inhibitors have simply been made to ‘look like’ the metabolite. In the author’s opinion, Fildes’s principle is unlikely to be very fruitful if we continue to confine ourselves to such naive pictorial analogies which are both not enough and too much. Pictorial analogy is not enough because an analogue may look like a metabolite and yet lack the chemical groupings necessary for combination with the appropriate enzyme; it leads us to overemphasize the geometry and underemphasize the chemistry of the molecule. Pictorial analogy is too much, since there may be a great deal in the structure of the metabolite which is not directly concerned in its attachment to the enzyme; it leads us to overload our inhibitors with possibly unnecessary complications. In order to model inhibitors more rationally on essential metabolites we must know two things, viz. the structure of the metabolite we are imitating and the precise way in which the metabolite combines with the bacterial enzyme to which it is related as substrate, co-enzyme or product.