Investigation of Allopurinol binding mechanism to allele HLA-A*33:03 by using Molecular Dynamics simulation

Abstract Allopurinol (ALP), a xanthine oxidase inhibitor, is an FDA-approved urate-lowering medication used to treat Gout, prevent tumor lysis syndrome, and prevent recurrent calcium nephrolithiasis in hyperuricosuria patients. However, it has been known as a common cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (HSS/DRESS), especially in patients carrying the Human Leukocyte Antigens allele HLA-B*58:01, which is more prevalent in Asian population. However, although patients do not carry the HLA-B*58:01 allele, they still exhibit allopurinol-induced SCAR. Surprisingly, a large number of these patients have the HLA-A*33:03 allele. In this research, we investigated the binding of ALP to the HLA-A*33:03 structure using Molecular Dynamics (MD) simulation. Our results showed that the complex of HLA-A*33:03 and ALP was stable after 100000 ps simulation time. ALP had strong interactions with three important residues locating in the active site of HLA-A*33:03, which include the seven amino acid residues Val 76, Asp 77, Leu 81, Ile 95, Gln 96, Asp 116, and Tyr 123. This data suggests that ALP has strong binding affinity for this allele. Thus, in addition to HLA-B*58:01, HLA-A*33:03 may be a potential screening marker before prescribing Allopurinol for Gout treatment.