Critical assessment of approaches for molecular docking to elucidate associations of HLA alleles with adverse drug reactions

Ramsbottom, Kerry A; Carr, Daniel F.; Jones, Andrew R.; Rigden, Daniel J.

doi:10.1016/j.molimm.2018.08.003

Cited by 16 publications

(12 citation statements)

References 54 publications

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“…In this study, the B � 38:02 model was created using templates with 95-98% identity with differing templates with similar identity being used for the other modelled structures created. Model selection is a very important aspect of molecular docking and can greatly impact the docking results seen [44]. This study was able to recreate similar docking results seen previously for B � 38:02 and B � 38:01, using our own modelled structures, whilst also incorporating docking results for the B � 27:05 risk allele and comparisons with selected control alleles.…”

Section: Discussionmentioning

confidence: 61%

“…It has previously been shown that the process and parameterisation of homology modelling may have an impact on the molecular docking results, compared to docking within a crystal structure [44]. It can be seen here that the control alleles favouring the F-pocket are generally the modelled structures, with the B � 15:01 and B � 51:01 known crystal structures showing favouring of the B-pocket.…”

Section: Molecular Dockingmentioning

confidence: 70%

“…seen between controls could be due to a number of factors including the homology modelling of the protein structures. As discussed in a previous study [44], homology modelling can impact the docking performance and inaccurate models could result in inaccurate docking results. Here, the similar alleles B � 38:02 (risk) and B � 38:01 (possible risk), with one mutated residue at position 80, were docked with both of the associated drugs.…”

Section: Discussionmentioning

confidence: 96%

“…Although the docking results for the risk alleles showed consistent results, with the risk alleles always favouring the F-pocket, the predicted poses for the control alleles showed some variation with some drug-allele combinations favouring the B-pocket and some favouring the F-pocket. Docking has previously been shown to be imperfect when considering these complex HLA cases [44], it is therefore understandable that the docking was unable to distinguish completely between risk and control for this case. Docking results are commonly reported as the most favourable pose, here we show a comparison of multiple runs as well as comparisons with selected control alleles.…”

Section: Discussionmentioning

confidence: 97%

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Informatics investigations into anti-thyroid drug induced agranulocytosis associated with multiple HLA-B alleles

et al. 2020

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Section: Discussionmentioning

confidence: 61%

Section: Molecular Dockingmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 97%

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Informatics investigations into anti-thyroid drug induced agranulocytosis associated with multiple HLA-B alleles

et al. 2020

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“…Based on our observations it is possible that AHS is driven by both the p-i and altered repertoire hypersensitivity model. We propose that conformational dynamics is a central tenet of all models of HLA-associated drug hypersensitivity, and should be characterized so as to complement crystallographic studies and in silico docking approaches 26 . The integration of such techniques, alongside the cellular studies and genetic associations reported to drugs, provides for a more comprehensive molecular and mechanistic insights into HLA-associated drug hypersensitivities.…”

Section: Discussionmentioning

confidence: 99%

The Role of Conformational Dynamics in abacavir-Induced Hypersensitivity Syndrome

Kass

Fodor

Riley

et al. 2017

Preprint

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Abacavir is an antiretroviral drug used to reduce human immunodeficiency virus (HIV) replication and decrease the risk of developing acquired immune deficiency syndrome (AIDS).However, its therapeutic value is diminished by the fact that it is associated with drug hypersensitivity reactions in up to 8% of treated patients. This hypersensitivity is strongly associated with patients carrying human leukocyte antigen (HLA)-B*57:01, but not patients carrying closely related alleles. Abacavir's specificity to HLA-B*57:01 is attributed to its binding site within the peptide-binding cleft and subsequent influence of the repertoire of peptides that can bind HLA-B*57:01. To further our understanding of abacavir-induced hypersensitivity we used molecular dynamics (MD) to analyze the dynamics of three different peptides bound to HLA-B*57:01 in the presence and absence of abacavir or abacavir analogues. We found that abacavir and associated peptides bind to HLA-B*57:01 in a highly diverse range of conformations that are not apparent from static crystallographic snapshots.Further, the presence of abacavir has a direct impact on the dynamics and the conformational space available to peptides bound to HLA-B*57:01, likely influencing abacavir-induced immune self-reactivity. Our results support hypersensitivity models in which abacavir-binding alters the equilibrium proportions of neopeptide conformations in a manner favourable to TCR binding. Our findings highlight the need to also consider the role of dynamics in understanding drug-induced hypersensitivities at the molecular and mechanistic level. This additional insight can help inform the chemical modification of abacavir to prevent hypersensitivity reactions in HLA-B*57:01+ HIV patients whilst retaining potent antiretroviral activity.

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Docking, Scoring, and Virtual Screening in Drug Discovery

Spyrakis

Sarkar

Kellogg

2021

Burger's Medicinal Chemistry and Drug Discovery

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Since its introduction about four decades ago, docking and scoring are now the very heart of structure‐based drug design. The past 10–20 years have seen a plethora of docking and scoring tools successfully integrated into drug discovery pipelines. Interestingly, while artificial intelligence is now receiving significant attention in the computational modeling arena, docking and scoring have long utilized these techniques. This comprehensive summary highlights some of the most significant achievements of docking and scoring, reviews the current status, provides descriptions of many of the tools available, comments on some of the outstanding challenges facing the paradigm, and offers perspectives and advice on best practices for users. While significant development is still needed in docking of flexible molecules and accurate Gibb's free energy predictions, docking and scoring are very useful when handled by experienced practitioners, but less so if treated as a “black box.” Lastly, we present a hypothetical case so beginners may appreciate the nuances of setting up a docking study. Focus in docking is now shifting toward parallel applications, i.e. protein–protein, protein–oligosaccharide, protein–DNA, or protein–RNA docking and polypharmacology. In summary, this article is intended to elucidate the nuances of the subject, while providing guidelines for practical implementation of effective workflows in drug discovery and structural biology.

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Critical assessment of approaches for molecular docking to elucidate associations of HLA alleles with adverse drug reactions

Cited by 16 publications

References 54 publications

Informatics investigations into anti-thyroid drug induced agranulocytosis associated with multiple HLA-B alleles

Informatics investigations into anti-thyroid drug induced agranulocytosis associated with multiple HLA-B alleles

The Role of Conformational Dynamics in abacavir-Induced Hypersensitivity Syndrome

Docking, Scoring, and Virtual Screening in Drug Discovery

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