RT Journal Article
SR Electronic
T1 STRUCTURAL ANALYSIS OF CYP2C9 AND CYP2C5 AND AN EVALUATION OF COMMONLY USED MOLECULAR MODELING TECHNIQUES
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1218
OP 1229
DO 10.1124/dmd.32.11.1218
VO 32
IS 11
A1 Afzelius, Lovisa
A1 Raubacher, Florian
A1 Karlén, Anders
A1 Jørgensen, Flemming Steen
A1 Andersson, Tommy B.
A1 Masimirembwa, Collen M.
A1 Zamora, Ismael
YR 2004
UL http://dmd.aspetjournals.org/content/32/11/1218.abstract
AB This work had two separate aims: to evaluate different modeling techniques and to make a detailed structural characterization of CYP2C9. To achieve these goals, the consensus principal component analysis (CPCA) technique and distance measurements were used to explore available crystal structures, newly built homology models, and repeated molecular dynamics simulations. The CPCA was based on molecular interaction fields focused on the active site regions of the proteins and include detailed amino acid analysis. The comparison of the CYP2C9 and CYP2C5 crystal structures revealed differences in the flexible regions such as the B-C and F-G loop and the N and C termini. Cross homology models of CYP2C9 and CYP2C5, using their respective crystal structures as templates, indicated that such models were more similar to their templates than to their target proteins. Inclusion of multiple templates slightly improved the similarity to the crystal target in some cases and could be recommended even though it requires a careful manual alignment process. The application of molecular dynamics simulations to highly flexible proteins such as cytochromes P450 is also explored and the information is extracted by the CPCA. Advantages and drawbacks are presented for the different modeling techniques. Despite the varying modeling success, the models give insight and understanding by the mutual forming and discarding of hypotheses. This is a dynamic process since the crystal structures are improving with time and, therefore, the answers to the models are also changing accordingly. The American Society for Pharmacology and Experimental Therapeutics