ReviewCompound lipophilicity for substrate binding to human P450s in drug metabolism
Section snippets
The P450 enzyme families
Each P450 enzyme family and subfamily exhibits selectivity for substrates of a particular type, although there can be a certain degree of overlap depending on the chemical class of compound in question [9]. Nevertheless, it is apparent that lipophilicity is fundamentally important to P450 substrate selectivity and binding affinity or clearance [10, 11, 12, 13], together with showing some influence on relative catalytic rate [14, 15]. Hansch and colleagues have published the details of several
Lipophilicity relationships in human P450 substrates
The role of compound lipophilicity in biological activity and related interactions [24, 25, 26, 27, 28] has been well established, particularly over the past 30 years, following the pioneering work of Corwin Hansch and Al Leo [29, 30]. More recently, the importance of lipophilic character to the success of drug discovery has been underscored in the well-known Lipinski ‘rule of five’ concept [31].
There have been several reports in the literature that point to the relevance of P450 substrate
Calculation of P450 substrate binding affinity and log P data
The general expression for estimating the binding affinity (ΔGbind) of P450 substrates can be formulated as follows [Equation 3]:
ΔGpart relates to the desolvation component obtained from the lipophilicity parameter log P, described previously; ΔGhb is the hydrogen bond component; ΔGπ-π is the π–π stacking interaction energy, and ΔGrot is the loss in individual bond rotational energy when a small substrate molecule binds to the P450 active site [19
Lipophilicity and P450 selectivity
The lipophilicity of the potential substrate is crucial for P450-mediated metabolism. In general, mammalian P450 substrates tend to possess log P values greater then zero and, in fact, there are few that have a negative log P. The likely reasons for this relate to membrane transport and substrate binding to the P450 active site, where desolvation of the haem environment hydrophobic ‘pocket’ usually represents the major contribution to binding affinity.
Human P450 enzymes display certain
Conclusions
In conclusion, therefore, it can be assumed that compound lipophilicity will play a major role in substrate binding to cytochromes P450 in mammalian systems and this will have an effect on the overall clearance of such compounds. By and large, the greater the value of log P for a chemical, the more avidly it will bind to a given P450 enzyme, although, after a certain point, binding affinity (and probably clearance) will start to fall with increasing log P, as the compound will become too
Acknowledgements
The financial support of GlaxoSmithKline Research and Development Limited, Merck Sharp and Dohme Limited and the University of Surrey Foundation Fund is gratefully acknowledged by DFVL. Miriam Jacobs would like to thank GlaxoSmithKline and BBSRC for their generous funding of a PhD studentship.
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