Structural bioinformatics analysis of CYP2D6 pharmacogenetic variation relevant to Sub-Saharan African

Sitabule, Blessing Rotondwa
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Pharmacogenomics is a field of study that involves the association of genes involved in drug metabolism with drug response. The CYP2D6 gene is important for drug metabolism. Different studies have identified a number of variations in the CYP2D6 gene in African populations with potential functional impact. The aim was to gain insights of how missense variants found in sub-Saharan African populations may potentially impact the functionality of the CYP2D6 enzyme, with focus on a drug commonly used in Africa. Fifty missense variants identified in African populations were selected using the PharmVAR, and GnomAD databases. Missense variants were prioritised for molecular dynamics using the Structural Workflow for Annotating ADME gene Targets (SWAAT) and the H3Africa dataset to identify variants that are more common in Africa and have a potential significant impact on drug metabolism. Missense variants which were exceptions to the prioritisation criterion were also selected for molecular dynamics assessments. The complex CYP2D6/thioridazines structure was used to run the molecular dynamics simulations as the reference structure and for the selected variants. A total of 10 missense variants were selected for molecular dynamics assessment. From the 10, only Y355C, P34S and R365H were destabilising according to all the SWAAT features. The MD results showed how the 10 missense variants may affect the stability, flexibility, secondary structure and mobility of the enzyme. These findings may be used to expand our knowledge in pharmacogenomics which may be used to enhance precision medicine in Africa.
A dissertation submitted in fulfilment of the requirements for the degree of Master of Science in Medicine to the Faculty of Health Science, School of Pathology, University of the Witwatersrand, Johannesburg, 2022