A MODEL OF ANTIMYCIN-A BINDING BASED ON STRUCTURE-ACTIVITY STUDIES OFSYNTHETIC ANTIMYCIN-A ANALOGS

The structural factors of antimycin A molecule required for inhibitory action were studied using newly synthesized antimycin A derivatives w ith bovine heart submitochondrial particles, in order to probe the int eraction between antimycin A and its binding site. In particular, we f ocused upon the roles of the amide bond bridge, which connects the sal icylic acid and dilactone ring moieties, and the 3-formylamino group i n the salicylic acid moiety. The lack of formation of an intramolecula r hydrogen-bond between phenolic OH and amide carbonyl groups resulted in a remarkable loss of the activity (by four orders of magnitude), i ndicating that this hydrogen-bond is essential for the inhibition. Thi s result suggested that both the phenolic OH and the carbonyl groups f orm a hydrogen-bond with some residues at a fixed conformation. In add ition, the inhibitory potency was remarkably decreased by N-methylatio n of the amide bond moiety, indicating that the NH group might functio n in hydrogen-bond interaction with the binding site. The N-methylatio n of 3-formylamino group also resulted in a decrease in the activity, probably due to a loss of the rotational freedom of this functional gr oup. Molecular orbital calculation studies with respect to the conform ation of the 3-formylamino group indicated that this group takes an ac tive conformation when the formyl carbonyl projects to the opposite si de of the phenolic OH group. Based upon a series of structure-activity studies of synthetic antimycin A analogues, we propose a tentative mo del for antimycin A binding in its binding cavity.