In vitro and in silico Approaches to Study Cytochrome P450-Mediated Interactions

Tan, Boon Hooi; Pan, Yan; Dong, A.; Ong, Chin Eng

doi:10.18433/j3434r

Cited by 8 publications

(4 citation statements)

References 31 publications

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“…Unfortunately, the majority of these assays only assess the rates of detoxification of standard substrates developed for use in model organisms or humans and do not assess how specific enzymes of herbivores detoxify the PSMs they encounter in natural forage. Even in human pharmacology, in vitro assays often do not predict in vivo outcomes (Karlsson et al 2013; Tan et al 2017). To our knowledge, no study has assessed whether the rate of detoxification of individual PSMs by metabolizing enzymes from wild vertebrate species can explain in vivo dietary preferences observed in the same species.…”

Section: Introductionmentioning

confidence: 99%

Preferences of Specialist and Generalist Mammalian Herbivores for Mixtures Versus Individual Plant Secondary Metabolites

et al. 2018

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Herbivores that forage on chemically defended plants consume complex mixtures of plant secondary metabolites (PSMs). However, the mechanisms by which herbivores tolerate mixtures of PSMs are relatively poorly understood. As such, it remains difficult to predict how PSMs, singly or as complex mixtures, influence diet selection by herbivores. Although relative rates of detoxification of PSMs have been used to explain tolerance of PSMs by dietary specialist herbivores, few studies have used the rate of detoxification of individual PSMs to understand dietary preferences of individual herbivores for individual versus mixtures of PSMs. We coupled in vivo experiments using captive feeding trials with in vitro experiments using enzymatic detoxification assays to evaluate the dietary preferences and detoxification capacities of pygmy rabbits (Brachylagus idahoensis), dietary specialists on sagebrush (Artemisia spp.), and mountain cottontails (Sylvilagus nuttallii), dietary generalists. We compared preference for five single PSMs in sagebrush compared to a mixture containing those same five PSMs. We hypothesized that relative preference for individual PSMs would coincide with faster detoxification capacity for those PSMs by specialists and generalists. Pygmy rabbits generally showed little preference among individual PSMs compared to mixed PSMs, whereas mountain cottontails exhibited stronger preferences. Pygmy rabbits had faster detoxification capacities for all PSMs and consumed higher concentrations of individual PSMs versus a mixture than cottontails. However, detoxification capacity for an individual PSM did not generally coincide with preferences or avoidance of individual PSMs by either species. Cottontails avoided, but pygmy rabbits preferred, camphor, the PSM with the slowest detoxification rate by both species. Both species avoided β-pinene despite it having one of the fastest detoxification rate. Taken together our in vivo and in vitro results add to existing evidence that detoxification capacity is higher in dietary specialist than generalist herbivores. However, results also suggest that alternative mechanisms such as absorption and the pharmacological action of individual mixtures of PSMs may play a role in determining preference of PSMs within herbivore species.

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Section: Introductionmentioning

confidence: 99%

Preferences of Specialist and Generalist Mammalian Herbivores for Mixtures Versus Individual Plant Secondary Metabolites

et al. 2018

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“…Although detoxification of any compounds can be studied by in vivo and in vitro assays on invertebrates and fish, in silico predictions have been previously used to reduce the number of such tests [34][35][36][37] . The approach used here is similar to other in silico prediction models for metabolism and toxicity, such as those provided by numerous ADMET software.…”

Section: Discussionmentioning

confidence: 99%

Computational ligands to VKORC1s and CYPs. Could they predict new anticoagulant rodenticides?

Bermejo-Nogales

Navas

Coll

2021

Preprint

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Anticoagulant-resistance in rodents and anticoagulant off-target effects are some of the world-wide problems of increasing concern. To search for new anticoagulant rodenticide candidates we have computationally explored some of the rat genes previously implicated in resistance to actual anticoagulants. In particular, we searched among hundreds of anticoagulant-similar chemotypes those binding rat wild-type VKORC1 (the best-known anticoagulant target, a Vitamin K-recycling enzyme), VKORC1L1 (a VKORC1-related enzyme), Cytochrome P450 CYP enzymes (some of the most important enzymes implicated in detoxification) and anticoagulant-resistant VKORC1-mutants (to minimize propensity to resistance). Results predicted new VKORC1 leads with binding-scores in the low nM range (high binding-affinities) predicting hydroxycoumarin- and naphtoquinone-like chemotypes. We then selected top-leads with additional high binding-scores to more than three anticoagulant-related CYPs, suggesting minimal detoxification rates and therefore maximal anticoagulation expectatives. A downsized list of top top-leads maintaining VKORC1 low-binding scores to anticoagulant resistant mutants, was finally proposed for experimental validation. The combination of different rat targets for computational studies, could be used to search for unrelated chemotypes, for reduction of off-target environmental anticoagulant impacts, and/or as new tools to explore anticoagulant molecular mechanisms.

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“…Therefore, the present study is focused on in silico analysis of IDO1 interacting proteins replace by using several computational tools which are linked to their functional, structural and physicochemical properties. In silico studies have been used for prediction of drug metabolism and interaction [19]. Such studies may add further information in the context of KP metabolites which related to neurological disorders like depression and helpful in therapeutics.…”

Section: Introductionmentioning

confidence: 99%

In-Silico Study of Protein-Protein Interaction, Secondary Structural Analysis and Annotation of Functional Domains of Indoleamine 2,3-Dioxygenase1

Tiwari,

Paramanik

2024

J Transl Med Transplant Res

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Indoleamine-2,3-dioxygenase-1 (IDO1) is the first catabolizing enzyme of tryptophan. IDO1 is extensively expressed in both immune and non-immune tissues and its activation is related to inflammation as well as severity of depressive symptoms, leading neurodegeneration and anxiety like behaviors. Moreover, IDO1 acts as novel immune checkpoint protein with regulatory pathways of immune response and may interact with several proteins. In this paper, physicochemical characterization, functional characterization, subcellular localization, secondary structural analysis and domains/motif/family of IDO1 interacting proteins were done using in silico tools such as STRING, ProtParam-Expasy, SOSUI, SOPMA and MOTIF Search. Eighteen interacting proteins were obtained by STRING. Briefly, all interacting proteins were hydrophilic in nature except AANAT. MAOA and MAOB were almost similar to each other and predicted as more stable in high range of temperature. Further, all interacting proteins showed diverse secondary structure. Higher percentage of α-helix structure was present in remaining proteins except KYNU, MAOA, IL4I1, MAOB and 4930438A08RIK. These proteins showed higher percentage of random coil. Moreover, almost equal percentage of α-helix and random coil were present in TPH1. Secondary structure β-turn was low in percentage in comparison to all other secondary structures. Taken together IDO1 interacting protein or enzyme which are involved in tryptophan catabolic process to kynurenine, serotonin synthesis, tryptophan metabolism, response to corticosterone and glucocorticoids, several other biological process. Such studies are useful to understand IDO1 dependent regulation in the context of tryptophan/kynurenine pathway and helpful in therapeutics of neurological disorders.

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In vitro and in silico Approaches to Study Cytochrome P450-Mediated Interactions

Cited by 8 publications

References 31 publications

Preferences of Specialist and Generalist Mammalian Herbivores for Mixtures Versus Individual Plant Secondary Metabolites

Preferences of Specialist and Generalist Mammalian Herbivores for Mixtures Versus Individual Plant Secondary Metabolites

Computational ligands to VKORC1s and CYPs. Could they predict new anticoagulant rodenticides?

In-Silico Study of Protein-Protein Interaction, Secondary Structural Analysis and Annotation of Functional Domains of Indoleamine 2,3-Dioxygenase1

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