A ligand-based model is reported that predicts the Ki values for cytochrome P450 2C9 (CYP2C9) inhibitors. This CoMFA model was used to predict the affinity of 14 structurally diverse compounds not in the training set and appears to be robust. The mean error of the predictions is 6 microM. The experimentally measured Ki values of the 14 compounds range from 0.1 to 48 microM. Leave-one-out cross-validated partial least-squares gives a q2 value of between 0.6 and 0.8 for the various models which indicates internal consistency. Random assignment of biological data to structure leads to negative q2 values. These models are useful in that they establish a pharmacophore for binding to CYP2C9 that can be tested with site-directed mutagenesis. These models can also be used to screen for potential drug interactions and to design compounds that will not bind to this enzyme with high affinity.
Hydrogen-transfer isomerization processes HCN ⇔ HNC: and HC≡CH ⇔ :C=CH 2 were studied in terms of bond order variations to understand the mechanism and asynchronous behavior of bond rearrangements by high quality ab initio calculations with TZ2p(d,f) basis sets. Bond orders were calculated from the TZ2p basis sets at the SCF level. Results from the bond order calculations clearly reveal that the migrating hydrogen when moves in curved paths that not only interact with the in plane π and π * orbitals of the triple bond (C≡C or C≡N) but also primarily causes the asynchronous behavior in the overall reaction mechanism. Overall advancement of the reaction in terms of individual bond-rearrangement processes on a relative footing is presented, which indicates the prime cause for the origin of activation barrier comes from the transforming multiple bonds in both these reactions. Easier computations of these bond indices not only reveal the significant insight into the importance of individual bonds during transformation, but also their application to larger systems.
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