Compound lipophilicity for substrate binding to human P450s in drug metabolism

doi:10.1016/S1359-6446(04)03115-0

Drug Discovery Today

Volume 9, Issue 12, June 2004, Pages 530-537

https://doi.org/10.1016/S1359-6446(04)03115-0 Get rights and content

Abstract

Compound lipophilicity is of key importance to P450 binding affinity and enzyme selectivity. Here, lipophilicity is discussed with reference to the human drug-metabolizing P450 enzymes of families CYP1, CYP2 and CYP3. From an extensive compilation of log P values for P450 substrates, and by analysis of relationships between partitioning energy and substrate-binding free energy, the relevance of lipophilicity and other factors pertaining to P450 binding affinity is explained, leading to the formulation of lipophilicity relationships within substrates of each human P450 enzyme involved in drug metabolism. Furthermore, log P values for P450 substrates appear to represent markers for enzyme selectivity. Together with the important roles of hydrogen bonding and π–π stacking interaction energies, the desolvation of the P450 active site makes a major contribution to the overall substrate-binding energy and, consequently, a good agreement with experimental information is reported based on this analysis.

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 (ΔG_bind) of P450 substrates can be formulated as follows [Equation 3]: $ΔG_{bind} = ΔG_{part} + ΔG_{hb} + ΔG_{π-π} + ΔG_{rot} + constant$

ΔG_part relates to the desolvation component obtained from the lipophilicity parameter log P, described previously; ΔG_hb is the hydrogen bond component; ΔG_π-π is the π–π stacking interaction energy, and ΔG_rot 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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ReviewCompound lipophilicity for substrate binding to human P450s in drug metabolism

Abstract

Section snippets

The P450 enzyme families

Lipophilicity relationships in human P450 substrates

Calculation of P450 substrate binding affinity and log P data

Lipophilicity and P450 selectivity

Conclusions

Acknowledgements

Biochem. Pharmacol

Eur. J. Pharm. Sci

Curr. Opin. Chem. Biol

Drug Discov. Today

Drug Discov. Today

Drug Discov. Today

Drug Discov. Today

Drug Discov. Today

Drug Discov. Today

Drug Discov. Today

Adv. Drug Deliv. Rev

Biochem. Pharmacol

Life Sci

Biochim. Biophys. Acta

Drug Discov. Today

Adv. Drug Deliv. Rev

J. Pharm. Sci

J. Mol. Biol

Forms and functions of cytochrome P450

Comp. Biochem. Physiol. C

Summary of information on human CYP enzymes: human P450 metabolism data

Drug Metab. Rev

Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers and inhibitors

Drug Metab. Rev

Inter-individual variations in human liver cytochrome P450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians

J. Pharmacol. Exp. Ther

Cytochrome P450 pharmacogenetics in drug development: in vitro studies and clinical consequences

Curr. Drug Metab

Human cytochromes P450 associated with the Phase 1 metabolism of drugs and other xenobiotics: a compilation of substrates and inhibitors of the CYP1, CYP2 and CYP3 families

Curr. Med. Chem

Baseline lipophilicity relationships in human cytochromes P450 associated with drug metabolism

Drug Metab. Rev

Quantitative structure-activity relationships of cytochrome P450

Drug Metab. Rev

QSAR of P450 oxidation: on the value of comparing kcat and Km with kcat/Km

Drug Metab. Rev

Estimating xenobiotic half-lives in humans from rat data: influence of log P

Environ. Health Perspect

Review
Compound lipophilicity for substrate binding to human P450s in drug metabolism

QSAR of P450 oxidation: on the value of comparing k_cat and K_m with k_cat/K_m