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Title: Structure-activity relationships (SAR) for cytochrome P4502C19
Author: Lock, Ruth E.
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1999
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Investigation of structure-activity relationships (SAR) for cytochrome P450 isoenzymes has implications for the prediction of drug-drug interactions. To date, the majority of research relating to the structure-activity relationships for P450 isoenzymes has concentrated on CYP2D6, CYP2E1, and CYP2C9. Knowledge of the likelihood of an interaction between a new chemical entity (NCE) and CYP2C19 is also of interest due to the existence of a genetic polymorphism in this enzyme. SAR for CYP2C19 were investigated in human liver microsomes (n=3) and CYP2C19 SUPERSOMESTM (n=2), by determining the inhibition of omeprazole 5-hydroxylation using benzodiazepine, phenytoin and fused-ring phenytoin analogues. (Fig. 8288). The inhibitory potency shown by the phenytoin and fused-ring phenytoin analogues appeared to be due to a combination of factors, including: a lipophilic group at R1, molecular length, surface area and volume of the compound (with the bulky fused-ring analogues showing greatest inhibitory potency), and lipophilicity (as indicated by calculated log P values and log D7.4 octanol values). A number of molecular features of the benzodiazepines proved important for the potent inhibition of CYP2C19-mediated omeprazole 5-hydroxylation. Again, a lipophilic group at R1 was essential. QSAR (quantitative structure-activity relationship) studies showed binding of the benzodiazepines to the active site of CYP2C19 to be governed by this area of lipophilicity. The carbonyl group was important for a CYP2C19 interaction. Benzodiazepines missing the function were not inhibitory. By superimposing chemically similar groups of the inhibitors, an overlay was created from their 3D structures using (S)-mephenytoin as a template. From the preliminary pharmacophore generated, a number of interactions with the CYP2C19 active site seem to be necessary for inhibitory potency. Hydrogen bond formation is possible between particular amino acid residues within the active site and the carbonyl groups of the inhibitory analogues. The aromatic rings are capable of interacting (perhaps via π-stacking interactions) with a number of corresponding lipophilic areas, possibly "pockets" within the CYP2C19 active site.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available