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Published on: December 21, 2019
Homology modelling of CYP3A4 from the CYP2C5 crystallographic template: analysis of typical CYP3A4 substrate
D F V Lewis1, B G Lake, M Dickins
1School of Biomedical and Molecular Sciences, University of Surrey, Guildford 2GU2 7XH, UK. d.lewis@surrey.ac.uk
Abstract:
1. The results of homology modelling of cytochrome P4503A4 (CYP3A4), which is a human enzyme of major importance for the Phase 1 metabolism of drug substrates, from the CYP2C5 crystal structure is reported. 2. The overall homology between the two protein sequences was generally good (46%) with 24% of amino acid residues being identical and a 22% similarity between matched pairs in the CYP3A4 and CYP2C5 aligned sequences, thus indicating that CYP2C5 represents a viable template for modelling CYP3A4 by homology. 3. The CYP3A4 model appears to show consistency with the reported findings from the extensive site-directed mutagenesis studies already published. 4. Typical CYP3A4 substrates, such as midazolam, testosterone, nifedipine and verapamil, are shown to fit the putative active site of the enzyme structure in a manner consistent with their known positions of metabolism.
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