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Relationships Between Pharmacovigilance, Molecular, Structural, and Pathway Data: Revealing Mechanisms for Immune-Mediated Drug-Induced Liver Injury.

Ho SS, McLachlan AJ, Chen TF, Hibbs DE, Fois RA - CPT Pharmacometrics Syst Pharmacol (2015)

Bottom Line: We present a novel approach that combines the methods of pharmacoepidemiology with in silico molecular modeling to identify specific features in toxic ligands that are associated with clinical features of IMDILI.Specifically, from pharmacovigilance data multivariate logistic regression identified 18 drugs associated with IMDILI (P < 0.00015).Subsequently, this information was combined with information from immune-pathway reviews and genetic-association studies and complemented with ligand-protein docking simulations to support a hypothesis implicating two putative targets within separate, possibly interacting, immune-system pathways: the major histocompatibility complex within the adaptive immune system and Toll-like receptors (TLRs), in particular TLR-7, which represent pattern recognition receptors of the innate immune system.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Pharmacy (A15), University of Sydney Sydney, NSW, Australia.

ABSTRACT
Immune-mediated drug-induced liver injury (IMDILI) can be devastating, irreversible, and fatal in the absence of successful transplantation surgery. We present a novel approach that combines the methods of pharmacoepidemiology with in silico molecular modeling to identify specific features in toxic ligands that are associated with clinical features of IMDILI. Specifically, from pharmacovigilance data multivariate logistic regression identified 18 drugs associated with IMDILI (P < 0.00015). Eleven of these drugs, along with their known and proposed metabolites, constituted a training set used to develop a four-point pharmacophore model (sensitivity 75%; specificity 85%). Subsequently, this information was combined with information from immune-pathway reviews and genetic-association studies and complemented with ligand-protein docking simulations to support a hypothesis implicating two putative targets within separate, possibly interacting, immune-system pathways: the major histocompatibility complex within the adaptive immune system and Toll-like receptors (TLRs), in particular TLR-7, which represent pattern recognition receptors of the innate immune system.

No MeSH data available.


Related in: MedlinePlus

Comparison between the docking of abacavir and penicilloic acid, a metabolite of flucloxacillin. (a,b) Abacavir and penicilloic acid respectively docked into HLA:B*5701 (3UPR). (c,d) Interaction of abacavir and penicilloic acid, respectively, with the amino acids in the binding pocket.
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fig04: Comparison between the docking of abacavir and penicilloic acid, a metabolite of flucloxacillin. (a,b) Abacavir and penicilloic acid respectively docked into HLA:B*5701 (3UPR). (c,d) Interaction of abacavir and penicilloic acid, respectively, with the amino acids in the binding pocket.

Mentions: Extra precision flexible docking showed that the metabolites of flucloxacillin were able to dock into abacavir's binding pocket. The pharmacophoric features are positioned to interact with complementary amino acid residues within the HLA binding groove. Furthermore, we demonstrated in silico that the penicilloic acid metabolites of flucloxacillin and of its 5-hydroxymethyl derivative contain structural features positioned to interact with all of the amino acid residues that were associated with abacavir binding as identified by Peters and co-workers28; specifically Tyr9, Tyr-74, Ile-95, Val97, Tyr99, Tyr123, Ile-124, Trp147, Ile3, Leu7, and Val9 (Figure4).


Relationships Between Pharmacovigilance, Molecular, Structural, and Pathway Data: Revealing Mechanisms for Immune-Mediated Drug-Induced Liver Injury.

Ho SS, McLachlan AJ, Chen TF, Hibbs DE, Fois RA - CPT Pharmacometrics Syst Pharmacol (2015)

Comparison between the docking of abacavir and penicilloic acid, a metabolite of flucloxacillin. (a,b) Abacavir and penicilloic acid respectively docked into HLA:B*5701 (3UPR). (c,d) Interaction of abacavir and penicilloic acid, respectively, with the amino acids in the binding pocket.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544056&req=5

fig04: Comparison between the docking of abacavir and penicilloic acid, a metabolite of flucloxacillin. (a,b) Abacavir and penicilloic acid respectively docked into HLA:B*5701 (3UPR). (c,d) Interaction of abacavir and penicilloic acid, respectively, with the amino acids in the binding pocket.
Mentions: Extra precision flexible docking showed that the metabolites of flucloxacillin were able to dock into abacavir's binding pocket. The pharmacophoric features are positioned to interact with complementary amino acid residues within the HLA binding groove. Furthermore, we demonstrated in silico that the penicilloic acid metabolites of flucloxacillin and of its 5-hydroxymethyl derivative contain structural features positioned to interact with all of the amino acid residues that were associated with abacavir binding as identified by Peters and co-workers28; specifically Tyr9, Tyr-74, Ile-95, Val97, Tyr99, Tyr123, Ile-124, Trp147, Ile3, Leu7, and Val9 (Figure4).

Bottom Line: We present a novel approach that combines the methods of pharmacoepidemiology with in silico molecular modeling to identify specific features in toxic ligands that are associated with clinical features of IMDILI.Specifically, from pharmacovigilance data multivariate logistic regression identified 18 drugs associated with IMDILI (P < 0.00015).Subsequently, this information was combined with information from immune-pathway reviews and genetic-association studies and complemented with ligand-protein docking simulations to support a hypothesis implicating two putative targets within separate, possibly interacting, immune-system pathways: the major histocompatibility complex within the adaptive immune system and Toll-like receptors (TLRs), in particular TLR-7, which represent pattern recognition receptors of the innate immune system.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Pharmacy (A15), University of Sydney Sydney, NSW, Australia.

ABSTRACT
Immune-mediated drug-induced liver injury (IMDILI) can be devastating, irreversible, and fatal in the absence of successful transplantation surgery. We present a novel approach that combines the methods of pharmacoepidemiology with in silico molecular modeling to identify specific features in toxic ligands that are associated with clinical features of IMDILI. Specifically, from pharmacovigilance data multivariate logistic regression identified 18 drugs associated with IMDILI (P < 0.00015). Eleven of these drugs, along with their known and proposed metabolites, constituted a training set used to develop a four-point pharmacophore model (sensitivity 75%; specificity 85%). Subsequently, this information was combined with information from immune-pathway reviews and genetic-association studies and complemented with ligand-protein docking simulations to support a hypothesis implicating two putative targets within separate, possibly interacting, immune-system pathways: the major histocompatibility complex within the adaptive immune system and Toll-like receptors (TLRs), in particular TLR-7, which represent pattern recognition receptors of the innate immune system.

No MeSH data available.


Related in: MedlinePlus