Effects of fexibility on the dynamics of ligand binding. Time course of action of muscarinic antagonists

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Abstract
In a study of the time course of action of structurally related rigid AF–41 and flexible AF-43 muscarinic antagonists it has been found that the onset binding contant kon of AF-43 is larger than that of AF-41 by about a factor of 3; the dissociation constant koff of AF-43, however, is almost 8 times larger than in the case of AF-41. The affinity, kon/koff, of the more rigid AF-41 is thus larger than that of the flexible AF-43. This agrees qualitatively with the results of two recent studies on other systems of ligands where the more rigid analogues are also found to have higher affinity. We develop a simple theory of local (site) bond formation which offers a possible explanation of the dependence of kon and koff of muscarinic antagonists on structural flexibility. General arguments are given to show that the increase in rigidity of a ligand can be expected to reduce kon, and to reduce koff even more, thus leading to higher affinity of the more rigid ligand. This effect of non-rigidity on the dynamics of bond formation and dissociation is general, and should also be observable in other systems. Some further important implications of the theory are also discussed.