Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

Andrade, Carolina Horta; Freitas, Lenis Medeiros de; Oliveira, Valéria de

doi:10.1590/s1984-82502011000200003

Cited by 15 publications

(5 citation statements)

References 92 publications

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“…Our laboratory has been working to overcome or reduce these failures, developing in silico tools to early predict and optimize some properties, such as metabolism [118–125], mutagenicity (Ames test), Caco-2 permeability, blood-brain barrier penetration (BBBP), and water solubility [126], skin sensitization, skin permeability, among others [127–131]. …”

Section: Discussionmentioning

confidence: 99%

Tuning hERG Out: Antitarget QSAR Models for Drug Development

Braga

Alves

Silva

et al. 2014

CTMC

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Several non-cardiovascular drugs have been withdrawn from the market due to their inhibition of hERG K+ channels that can potentially lead to severe heart arrhythmia and death. As hERG safety testing is a mandatory FDA-required procedure, there is a considerable interest for developing predictive computational tools to identify and filter out potential hERG blockers early in the drug discovery process. In this study, we aimed to generate predictive and well-characterized quantitative structure–activity relationship (QSAR) models for hERG blockage using the largest publicly available dataset of 11,958 compounds from the ChEMBL database. The models have been developed and validated according to OECD guidelines using four types of descriptors and four different machine-learning techniques. The classification accuracies discriminating blockers from non-blockers were as high as 0.83–0.93 on external set. Model interpretation revealed several SAR rules, which can guide structural optimization of some hERG blockers into non-blockers. We have also applied the generated models for screening the World Drug Index (WDI) database and identify putative hERG blockers and non-blockers among currently marketed drugs. The developed models can reliably identify blockers and non-blockers, which could be useful for the scientific community. A freely accessible web server has been developed allowing users to identify putative hERG blockers and non-blockers in chemical libraries of their interest (http://labmol.farmacia.ufg.br/predherg).

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Section: Discussionmentioning

confidence: 99%

Tuning hERG Out: Antitarget QSAR Models for Drug Development

Braga

Alves

Silva

et al. 2014

CTMC

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“…The tested anti‐HIV agents 1 – 6 are bulky, have a high molecular weight (505.6–720.9 g/mol) and contain a hydroxyethylene group which is responsible for the inhibition of HIV protease . CYP105D and CYP107Z accept all tested compounds 1 – 6 (Figure A).…”

Section: Resultsmentioning

confidence: 99%

Two‐step Screening for Identification of Drug‐metabolizing Bacterial Cytochromes P450 with Diversified Selectivity

et al. 2020

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The evaluation of drug metabolites is compulsory during drug development. Since recently, bacterial cytochromes P450 and their mutated variants have attracted considerable interest as an alternative to hepatic P450s for the synthesis of human drug metabolites. Thus, straightforward screening approaches are required that enable rapid identification and evaluation of drug‐metabolizing bacterial P450s with different product selectivities. Herein, we report a two‐step screening method for discovery and characterization of new P450s from actinomycetes that enable oxidation of various drugs. In the first step, substrate profiling with three structurally different model drugs, ritonavir, testosterone, amitriptyline, allowed us to select CYP105D and CYP107Z from Streptomyces platensis DSM 40041 that accepted all model substrates and produced human‐like drug metabolites. In the second step, activity tests with an array of 25 structurally‐related molecules and derivatives of the three model compounds revealed a correlation between structural variations in the target drugs and the enzyme chemo‐ and regioselectivity.

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“…The pathogenesis of idiosyncratic DILI has often been related to CYP dependent drug metabolism, although the respective DILI was not assessed regarding causality for the drug under consideration study, nor was there any verification that the drug was really metabolized by CYP, and the CYP isoform involved in the metabolism of the drug commonly remained unconsidered. Based on published data [ 64 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 ], a recent analysis on drugs most implicated in idiosyncratic DILI assessed by RUCAM showed that only a portion of the drugs were substrates of hepatic microsomal CYP ( Table 3 ) [ 54 ].…”

Section: Overview On Molecular Toxicology In Human Idiosyncratic Dilimentioning

confidence: 99%

Molecular Idiosyncratic Toxicology of Drugs in the Human Liver Compared with Animals: Basic Considerations

Teschke

2023

IJMS

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Drug induced liver injury (DILI) occurs in patients exposed to drugs at recommended doses that leads to idiosyncratic DILI and provides an excellent human model with well described clinical features, liver injury pattern, and diagnostic criteria, based on patients assessed for causality using RUCAM (Roussel Uclaf Causality Assessment Method) as original method of 1993 or its update of 2016. Overall, 81,856 RUCAM based DILI cases have been published until mid of 2020, allowing now for an analysis of mechanistic issues of the disease. From selected DILI cases with verified diagnosis by using RUCAM, direct evidence was provided for the involvement of the innate and adapted immune system as well as genetic HLA (Human Leucocyte Antigen) genotypes. Direct evidence for a role of hepatic immune systems was substantiated by (1) the detection of anti-CYP (Cytochrome P450) isoforms in the plasma of affected patients, in line with the observation that 65% of the drugs most implicated in DILI are metabolized by a range of CYP isoforms, (2) the DIAIH (drug induced autoimmune hepatitis), a subgroup of idiosyncratic DILI, which is characterized by high RUCAM causality gradings and the detection of plasma antibodies such as positive serum anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA), rarely also anti-mitochondrial antibodies (AMA), (3) the effective treatment with glucocorticoids in part of an unselected RUCAM based DILI group, and (4) its rare association with the immune-triggered Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) caused by a small group of drugs. Direct evidence of a genetic basis of idiosyncratic DILI was shown by the association of several HLA genotypes for DILI caused by selected drugs. Finally, animal models of idiosyncratic DILI mimicking human immune and genetic features are not available and further search likely will be unsuccessful. In essence and based on cases of DILI with verified diagnosis using RUCAM for causality evaluation, there is now substantial direct evidence that immune mechanisms and genetics can account for idiosyncratic DILI by many but not all implicated drugs, which may help understand the mechanistic background of the disease and contribute to new approaches of therapy and prevention.

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Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

Cited by 15 publications

References 92 publications

Tuning hERG Out: Antitarget QSAR Models for Drug Development

Tuning hERG Out: Antitarget QSAR Models for Drug Development

Two‐step Screening for Identification of Drug‐metabolizing Bacterial Cytochromes P450 with Diversified Selectivity

Molecular Idiosyncratic Toxicology of Drugs in the Human Liver Compared with Animals: Basic Considerations

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