Research On The Mechanism Of Abacavir-induced SADR

Abacavir is a nucleoside reverse transcriptase inhibitor in the treatment of HIVinfection. Abacavir can induce serious adverse drug reaction (SADR) by involvingdrug-specific T-cells. Recently, GWAS (Genome-Wide Association Study) showed thatthere is a strong association between Abacavir-induced SADR and human leukocyteantigen-B*5701(HLA-B*5701). Due to the lack of crystal structure ofAbacavir-HLA-B*5701-peptide, the underlying mechanism of this association remainsunknown. In the light of experimental observations, molecular docking and dynamicsimulations were employed to explore the non-covalent interactions between Abacavirand HLA-B*5701as well as the mechanism of Abacavir-induced SADR. The studies inthis paper are of great significance in exploring the mechanisms of HLA-associatedSADR and drug safety evaluations. The main results are listed as follows:â‘ Peptide binding specificities of HLA-B*5701and B*5801: VHSE (PrincipalComponent Score Vector of Hydrophobic, Steric, and Electronic Properties), a set ofamino acid structural descriptors, was employed to establish QSAR (QuantitativeStructural-Activity Relationships) models of peptide binding affinities of HLA-B*5701and B*5801. Optimal linear SVM (Support Vector Machine) models with highpredictive capabilities were obtained for both B*5701and B*5801. The R2(Coefficientof Determination), Q2(Cross-Validated R2), and Rpre2(R2of Test Set) of two optimalmodels were0.7530,0.7037,0.6153(B*5701) and0.6074,0.5966,0.5762(B*5801),respectively. For B*5701and B*5801, the mutations in positions45(Met-Thr) and46(Ala-Glu) have little influence on the selection specificity of the P2position of thebound peptide. However, the mutation in position97(Val-Arg) greatly influences theselection specificity of the P7position. HLA-B*5701prefers the bulky and positivelycharged amino acids (Arg, His, Lys) at the P7position. In contrast, HLA-B*5801prefers the non-polar hydrophobic amino acids at the P7position while positivelycharged amino acids are unfavored.â‘¡Surflex-dock was used to explore the potential non-covalent interactionsbetween1238drugs with HLA-B*5701, HLA-B*5702, HLA-B*5703, andHLA-B*5801. Results showed that the docking scores of Abacavir are in the range of5-6for4HLA alleles. When docked into HLA-B*5701, Abacavir can interacts with Thr73, Tyr9and Ser3of bound peptide by H-bond interactions. This mode was similar to the case of HLA-B*5702and HLA-B*5703. In the case of B*5801, Abacavir binds tothe surface of the peptide binding groove by H-bond interaction with Arg65. Moreover,Abacavir metabolites, analogs, and other drugs are, in the most case, bound to thesurface of peptide binding groove by H-bond interactions with HLA and bound peptide.â‘¢In the light of molecular docking studies, molecular dynamic simulation wasused to explore dynamic interactions of Abacavir with HLA-B*5701-LF9. The resultsof MD showed that, after20ns MD simulation, Abacavir can bind to the bottom of theantigen-binding cleft and interacte with one key residue Asp114located in F pocket.The influnce of position7(P7) and position9(P9) on the interactions of Abacavir withHLA-B*5701-LF9were also studied by amino acid mutation. The results indicated thatAbacavir can not competitively bind to F pocket by interaction with Ser116. Thereasonable explanation is that the MD simuations may fall into the trap of local energyminima.â‘£Molecular dynamic simulation of Abacavir-HLA-B*5701-RI10: Moleculardocking and dynamic simulation were used to model Abacavir-HLA-B*5701-RI10complex. The results showed that there is a pocket on the surface of HLA-B*5701-RI10complex, which can accommodate small molecules, such as Abacavir. Based on thedocking results,25ns MD simulation were performed on Abacavir-HLA-B*5701-RI10complex. By superposition of the lowest energy conformation on3vri, the RMSD ofHLA backbone atoms was only2.9. The results showed that Abacavir may bindcompetitively to E pocket and F pocket by interactions with Asp114and Ser116ofHLA-B*5701, which alters the repertoire of bound peptides and causes the incident ofSADR.