CYP ligand interactions

MD simulations are used in various ways to study CYP-ligand interactions. As shown in Table 1, applications for homology model optimization and validation of model stability and the prediction of sites of catalysis in substrates are becoming common practice. Prediction of substrate and inhibitor binding affinity and orientation have been reliable in the cases of CYP101 (cam), 2B4, and 1 Al, and combined with QM calculations on the substrate for predictions of product formation for CYP101 (cam), 102 (BM3), 107A (EryF), and 2E1. 

Several kinetic parameters can be measured on different experimental systems to account for the interaction of a compound with CYPs. For example when studying the metabolic stability of a compound, it could be measured in a recombinant CYP system, in human liver microsomes, in hepatocytes and so on. Each system increases in biological complexity. Although in the recombinant CYP system only the cytochrome under consideration is studied, in the case of the human liver microsomes, there is a pool of enzyme present that includes several CYPs, and finally in the hepatocyte cell system, metabolizing enzymes play an important role in the metabolic compound stability. In addition, transport systems are also present that could involve recirculation or other transport phenomena. The more complex the experimental system, the more difficult it is to extract information on the protein/ligand interaction, albeit it is closer to the in vivo real situation and therefore to the mechanism that is actually working in the body. 

By comparing the evolution of homology models of the CYPs and what we have learned from them with available experimental structures, we will be able to objectively assess the impact homology models have had on the understanding of protein-ligand interactions. In particular, as a case study we will focus... 

However, simple knowledge of the inhibition mechanism or inhibition level is not helpful in designing a safer compound. Researchers need to understand why a specific compound leads to MBI at the molecular level to design a safer compound. This can be achieved only by understanding which molecular group is exposed to the CYP-heme, to make ligand-heme interactions more difficult (Figure 12.1). 

Once the protein interaction pattern is translated from Cartesian coordinates into distances from the reactive center of the enzyme and the structure of the ligand has been described with similar fingerprints, both sets of descriptors can be compared [25]. The hydrophobic complementarity, the complementarity of charges and H-bonds for the protein and the substrates are all computed using Carbo similarity indices [26]. The prediction of the site of metabolism (either in CYP or in UGT) is based on the hypothesis that the distance between the reactive center on the protein (iron atom in the heme group or the phosphorous atom in UDP) and the interaction points in the protein cavity (GRID-MIF) should correlate to the distance between the reactive center of the molecule (i.e. positions of hydrogen atoms and heteroatoms) and the position of the different atom types in the molecule [27]. 

The second mechanism of inhibition occurs with the slow reversible ligand binding of a nucleophilic electron pair to the heme iron of the CYP. These types of interactions can occur with anilines, phenols, and several of the nitrogen- or oxygen-containingaromatic heterocycles (pyridines and imidazoles, etc.), provided the rest of the molecule is sufficiently lipophilic. Whether inhibition occurs with a specific compound depends on the electronic and steric effects of substituents close to the electron pair. Imidazoles provide a good exam-... 

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