Computational prediction of drug binding and rationalisation of selectivity towards cytochromes P450.
BACKGROUND
Early in-vitro consideration of metabolism and inhibition of cytochrome P450 has proven its merits over the last 15 years. Simultaneously, many computational drug-design methods have been developed, and are being applied to study the interactions between drug candidates and cytochrome P450 enzymes (P450s).


OBJECTIVE
This review discusses the recent advances of these methods and the implications that are specific for P450s.


METHODS
Mainly focusing on the prediction of binding affinity and ligand selectivity, we outline the applicability of the different methods to answer specific questions. Special emphasis is put on the different levels of theory that are being used in recent computational descriptions of ligand-P450 interactions.


CONCLUSIONS
P450s offer an additional challenge for computational methods, considering the ambiguities of the catalytic cycle and the significant flexibility of the active site. Different computational methods display different limitations, which is crucial to take into account when choosing the method appropriate to each application.
Stjernschantz
Eva
E
Vrije Universiteit Amsterdam, Leiden/Amsterdam Centre for Drug Research, Division of Molecular Toxicology, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Vermeulen
Nico P E
NP
Oostenbrink
Chris
C
D000818:Animals; D001711:Biotransformation; D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005544:Forecasting; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System