Idiosyncratic adverse drug reactions (ADR) are detrimental effects patients can suffer from after taking a particular medication. Such type of immune-based ADRs are mostly triggered by drugs directly binding to human leukocyte antigen (HLA) proteins. Interestingly, the HLA-B*57:01 variant has been reported to bind with abacavir, flucloxacillin, and pazopanib inducing either abacavir hypersensitivity syndrome (AHS) or drug induced liver injury (DILI). Recently, we developed a virtual screening model using structure-based molecular docking to forecast a drug’s ability to bind with the HLA-B*57:01 variant using three X-ray crystals (PDB: 3VRI, 3VRJ, 3UPR). In this new study, we used our model to screen the DrugBank library containing over 7,000 drugs and drug candidates at the time of this study. Drugs were considered potentially HLA liable if they afforded a Glide docking score (DS) <u>&lt;</u> -7 kcal/mol and eModel score (eM) <u>&lt;</u> -50 kcal/mol. Due to the limited number of known true HLA-B*57:01 actives, two screening approaches were employed referred to as Filter 1 and Filter 2. Filter 1 identified 620 HLA-B*57:01 active compounds that were then analyzed by DS, eM, binding mode, and similarity to abacavir. From our earlier work, it was determined that the co-binding peptide had a significant impact upon a drug’s ability to bind with HLA-B*57:01. In order to account for the role of peptide upon binding a second screening method was adopted: Filter 2 used the X-ray crystals 3VRI, 3VRJ, and 3UPR with the peptides P1, P2, and P3, respectively. Filter 2 identified drugs that showed activity in presence of all three peptides using both SP and XP scoring functions. Our presentation will focus on analyzing the top drugs retrieved using both Filters 1 and 2, their binding modes, and overall properties. This work is of high relevance for Precision Medicine.

Adverse drug reactions triggered by the common HLA-B*57:01 variant: Virtual screening of DrugBank

253rd National Meeting (2017)

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