The discovery of captopril as a potent, orally active inhibitor of angiotensin-converting enzyme (ACE) led to the recent development of many series of novel structures with similar biological activity. To date, however, all of these inhibitors are flexible or semiflexible molecules, and there is therefore no clear definition of the conformational requirements for ACE inhibition. In an effort to solve this problem, we have carried out conformational energy calculations on a series of eight structurally diverse ACE inhibitors. Comparison of the low-energy conformations available to these molecules leads to the conclusion that there is a common low-energy conformation throughout the series. The calculations thus define the structural and conformational requirements for ACE inhibition. Expansion of this model to the receptor level has been achieved by considering possible alternative receptor sites for each of the molecules in its proposed biologically active conformation and leads to an active-site model for ACE which may be useful for the design of further inhibitors.
Molecular orbital calculations are used to describe the reaction surface for the non-enzymic Claisen rearrangement of chorismate to prephenate, which may proceed through either a boat-like or a chair-like transition state. Detailed molecular geometries are obtained for the neutral and dianionic forms of chorismate, prephenate, and the alternative transition states. The transition states are asymmetric structures in which the breaking C-O bond (c. 1.45 A) is significantly shorter than the making C-C bond (c. 1.95 A). The alternative reaction pathways have almost identical enthalpies of activation (chair, 277.4 kJ/mol ; boat, 282.8 kJ/mol; dianionic forms) which result partly from a loss of internal bond strength and partly from repulsive interactions between the polar carboxyl groups. Protonation stabilizes the transition states (chair, 247.3 kJ/mol; boat, 248.5 kJ/mol ; diacid forms) by delocalization of charge in the carboxyl groups, and a similar mechanism is proposed for the greatly reduced enthalpy of activation in aqueous solution (86.6 kJ/mol). The enthalpy difference between the alternative reaction pathways is insufficient to define a preferred transition state structure, and either pathway may be favoured for the non-enzymic reaction in aqueous solution. For the enzyme-catalysed reaction the chair pathway is used, and the calculated transition state structures and enthalpy barriers provide information relevant to the catalytic mechanism. They indicate that an active site comprising only two essential binding groups is sufficient to account for catalysis; the orientation of these groups within the active site should allow simultaneous bond formation, accompanied by charge delocalization, to both carboxyl groups of the transition state, but not to those of substrate or product. The calculated structure for the chair transition state, taken in conjunction with those for chorismate and prephenate, thus provides a template for the active sites of chorismate mutases.
Conformational flexibility round the diphenyl ether linkage in the thyroid hormones has been investigated by means of molecular orbital (AM1) and classical potential-energy calculations. The results obtained from these theoretical approaches are in qualitative agreement with those from n.m.r. spectroscopy, i.e., the barrier to rotation around this structural feature is sufficiently low to allow rapid interconversion between two stable conformers to occur at room temperature. Two pathways of rotation around the diphenyl ether bridge were explored and were both calculated to be approximately 14-15 kJ mol-1 by the AM1 method. This compares with the experimental barrier of 36 kJ mol-1. The potential-energy calculations gave barriers up to an order of magnitude larger which were inconsistent with experimental observations. A comparison of the AM1 data with results from previous studies with CNDO/2, which predicted a larger barrier, is also given. The detailed mode of interconversion around the two torsion angles involved in diphenyl ether rotation is investigated, as is the interplay of the bulky iodo substituents with the second aromatic ring during such conformational changes. The nature of torsion angle cooperation during rotations around this linkage is discussed.
We report the synthesis of a series of disubstituted 4,5- diphenylpyridine-2,6(1H,5H)- diones (8),(10),(12)-(21), their characterization by 1H and 13C n.m.r . spectroscopy and their receptor binding affinities for catecholamine and benzodiazepine receptors.
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