Abstract Description

A CYP2 family enzyme, Cytochrome P450 2D6 (CYP2D6), contributes to the metabolism of at least 25 % of medical drugs on the market today, positioning it as a major enzyme in pharmacogenomic research. Therefore, studies on this enzyme and its variants are vital for the future development of personalized medical therapies. In this study, investigations on CYP2D6 were conducted to further 3D pharmacogenomic research on this particular enzyme, with an emphasis on African populations that have historically been underrepresented in this field. Afrocentric CYP2D6 alleles (*149, *152, *153, *154, *155, *157, *159, *160, *162 and *163), obtained from Niger–Congo language speaking African participants, were identified in PharmVar. These alleles currently have no known clinical function. Building on mechanisms we identified previously, this study aimed to predict their potential functional impact. Molecular dynamic (MD) simulations for all systems were conducted at the Centre for High Performance Computing (CHPC). Post MD analysis was then performed, including RMSD, RMSF, Rg, conformational clustering and DSSP calculations to assess the secondary structural stability, conformation, and flexibility changes in the Afrocentric CYP2D6 alleles. Hydrogen bond calculations were employed to observe the overall changes in interactions between the residues within the different allele systems. The heme area within the catalytic site was also analyzed, to observe if variation presence had affected the stability of this region. Finally, channel analysis along with dynamic residue network analysis was utilized to observe changes in tunnel opening due to variations, and how this affected the communication pathways within the enzymes. Results from these analyses were then compared to the mechanisms, and overall, there was a prediction of reduced activity among some of the CYP2D6 Afrocentric alleles studied here.