Harvesting Candidate Genes Responsible for Serious Adverse Drug Reactions from a Chemical-Protein Interactome

Abstract

Identifying genetic factors responsible for serious adverse drug reaction (SADR) is of critical importance to personalized medicine. However, genome-wide association studies are hampered due to the lack of case-control samples, and the selection of candidate genes is limited by the lack of understanding of the underlying mechanisms of SADRs. We hypothesize that drugs causing the same type of SADR might share a common mechanism by targeting unexpectedly the same SADR-mediating protein. Hence we propose an approach of identifying the common SADR-targets through constructing and mining an in silico chemical-protein interactome (CPI), a matrix of binding strengths among 162 drug molecules known to cause at least one type of SADR and 845 proteins. Drugs sharing the same SADR outcome were also found to possess similarities in their CPI profiles towards this 845 protein set. This methodology identified the candidate gene of sulfonamide-induced toxic epidermal necrolysis (TEN): all nine sulfonamides that cause TEN were found to bind strongly to MHC I (Cw*4), whereas none of the 17 control drugs that do not cause TEN were found to bind to it. Through an insight into the CPI, we found the Y116S substitution of MHC I (B*5703) enhances the unexpected binding of abacavir to its antigen presentation groove, which explains why B*5701, not B*5703, is the risk allele of abacavir-induced hypersensitivity. In conclusion, SADR targets and the patient-specific off-targets could be identified through a systematic investigation of the CPI, generating important hypotheses for prospective experimental validation of the candidate genes.

HLA Haplotype Determines Hapten or p-i T Cell Reactivity to Flucloxacillin

“…In this context, noncovalent interactions of drugs with HLA molecules have been investigated in several studies. Carbamazepine binds to the surface of HLA-B*15:02 molecules (14), whereas abacavir was shown to interact within the peptide-binding groove of HLA-B*57:01 molecules (15), modifying the property for peptide binding (16)(17)(18). This study aims at elucidating the mechanism of FLUX presentation and T cell stimulation by FLUX.…”

Studies on abacavir-induced hypersensitivity reaction: a successful example of translation of pharmacogenetics to personalized medicine

“…On the other hand, based on prior knowledge in protein-drug interaction and data mining, an in silico approach was proposed by Yang et al [41] to explain the underlying mechanisms of adverse drug reactions through specific protein-drug interactions. By analyzing the binding strength and binding conformation changes among 162 drug molecules and 845 proteins, they predicted the specific binding interaction between abacavir and HLA-B*57:01 molecule (not HLA-B*57:03) mediates skin hypersensitivity.…”

Delayed drug hypersensitivity: models of T‐cell stimulation

“…Since many different proteins might be modified, the resulting clinical picture might be as variable as with real haptens and SMX is indeed known to cause many different types of diseases affecting many organs (exanthems, anaphylaxis, SJS, hepatitis, etc.). These + T-cell responses: the drug (shown as abacavir in this example) binds avidly, but non-covalently to allele specific HLA-B determinants [45].This binding may stabilize the HLA-complex even without peptide. A CD8 + T-cell reaction against this drug-HLA complex will be developed.…”

“…Some severe drug hypersensitivity reactions caused by certain drugs have a strikingly high HLA-B-allele association [40][41][42]. For example, in the case of abacavir hypersensitivity, a drug hypersensitivity syndrome strongly associated with the HLA-B*5701 allele [43], key interacting residues in the HLA-B*5701 peptide binding cleft could be identified [44], which allow the formation of non-covalent interactions with the drug abacavir [45]. Recent in silico data published by Yang et al suggest that drugs could also fit in 'empty' , non-peptide bearing MHC class I molecules.…”