STRUCTURAL DETERMINANTS OF CYTOCHROME-P450 SUBSTRATE-SPECIFICITY, BINDING-AFFINITY AND CATALYTIC RATE

The structural characteristics of cytochrome P450 substrates are summa rised, showing that molecular descriptors can discriminate between che micals of differing P450 isozyme specificity. Procedures for the estim ation of P450 substrate binding interaction energies and rates of meta bolism are described, providing specific examples in both individual c ompounds binding to P450s, including those of known crystal structure, and within series of structurally related chemicals. It is demonstrat ed that binding energy components are primarily hydrophobic/desolvatio n and electrostatic/hydrogen-bonded in nature, whereas electronic fact ors are of importance in determining variations in reaction rates. It is thus shown that the prediction of P450 substrate binding affinities and catalytic rates may be feasible, provided that sufficient structu ral information is available for the relevant enzyme-substrate complex . (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.