Active site structures of mechanism-based inhibitors of mammalian adenylyl cyclase are calculated from templates based on theoretical structures of the native reaction path bound in the active site. Adenine specificity is maintained for all calculated analogues along the reaction path. Reaction was initiated by autocatalytic activation of the 3'OH of the ribose by the desolvated &Alpha phosphate. Stabilization of the developing charge on the 3'O primarily by MgA in the intermediate and transition state then lowers the activation energy. This mechanism is explored in reactant analogue inhibitor structures for the deoxy 3'OH, the deoxy 2'OH group, the P&Alpha thiophosphate, and adenosine 5' phosphonate. The calculated structures for all reactive analogues find the 3'OH hydrogen-bonded to the &Alpha phosphate in position for the abstraction of the 3'H. In order to follow reactive behavior, binding of the concomitant intermediate analogue in the active site for some of these examples is also calculated.

One set of product analogues is based on an experimentally observed class of potent inhibitors consisting of adenine bound to hydroxamic acid through various flexible linkers. The dissociation of the proton from the hydroxamate to produce a potent metal binder within the active site suggests analogous groups such as a sulfonamide can reach the enzyme as a neutral molecule but bind ionically as a product analogue within the active site.