Relationships Between Chemical Structure and Biological Activity
Alfred Burger, A P Parulkar · Annual Review of Pharmacology · 1966
By ALFRED BURGER AND ANILKUMAR P. PARULKAR Department of Chemistry, University of Virginia, Charlottesville, Virginia The readers of these Annual Reviews have been presented with several articles on relations of chemical structure to biological activity in the last few years. Among them were the superb and comprehensive review by Bloom & Laubach (1) and the interesting synopsis by Fastier (2) . Neither the biochemically based nor the heuristic approach to explana tions of such relationships has advanced startlingly in the last two years, although many problems have been focused more sharply. The present survey is therefore an expansion and reconsideration of some of the same topics from a medicinal-chemical point of view. A number of analyses of structure-activity relation s have appeared elsewhere. Some of them concern broad principles and are based on care ful physicochemical measurements (2-7) . Other reviews of the same subject restrict themselves to one series of structurally related compounds (8) or of compounds exerting similar biological activities (9, 10). Al most all of the authors of these reviews, and many others before them, have expressed the hope that a clear understanding of bioreceptors would go a long way in eliminating the high percentage of failures in drug de sign. These failures are due to our empirical approach to medicinal sci ence. Even in situations in which relations of compounds of apparently identical biological activity, measured in the same test system, are sup ported by similar relations of one or two physical properties, the question remains whether these particular physical properties have anything to do with the biological performance of the compounds. Yet nobody can deny that it would be of great value to be able to describe exactly what goes on in the interaction of a drug with a reactive cellular constituent. It appears appropriate, therefore, to comment briefly on the present state of our knowledge in this area. Theories and explanations prove their worth only if they permit pre dictions and extrapolations. The medicinal scientist is confronted with the unabating need for new drugs for unsolved therapeutic problems; their discovery, evaluation, and useful development compete for his at tention to fundamental principles of drug action. There is no point in dwelling on methods of chance discovery of therapeutic agents by ran dom screening or by the accidental observation of a biological effect, al though our knowledge of structure-activity relationships is enriched by