The challenges of in silico contributions to drug metabolism in lead optimization.
BACKGROUND
The site of metabolism (SOM) predictions by CYP 3A4 are extremely important during the drug discovery process especially during the lead discovery or library design phases. With the ability to rapidly characterize metabolites from these enzymes, the challenges facing in silico contribution change during the drug optimization phase. Some of the challenges are addressed in this article. Some aspects of the SOM prediction software and methodology are discussed in this opinion article and examples of software utility in overcoming metabolic instability in drug optimization are shown.


METHODS
SOM prediction by various approaches is discussed. Two ways of overcoming metabolic instability, blocking the metabolic softspots and rational modification of the instable molecule to avoid interaction with the CYP pocket, are discussed. The contribution plot in MetaSite and its use are discussed.


RESULTS
The reader will gain an understanding of possible approaches to either blocking the metabolic softspot or rationally modifying the molecule using MetaSite software or docking approaches. Blocking metabolism using fluorination has risks especially introducing multifluorinated benzene rings in the molecule.


CONCLUSIONS
During the lead optimization phase of drug discovery, when metabolic instability is an issue in a series, in silico approaches can be used to modify the molecule in order to decrease clearance due to metabolism, even that due to CYP3A4.
Vaz
Roy J
RJ
Structure, Design, Informatics, Sanofi-Aventis US, 1041 Rt 202/206N, Bridgewater, NJ 08807, USA. roy.vaz@sanofi-aventis.com
Zamora
Ismael
I
Li
Yi
Y
Reiling
Stephan
S
Shen
Jian
J
Cruciani
Gabriele
G
D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000639:trends; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*
D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human