Modeling ADMET

Ghosh, Jayeeta; Lawless, M.; Gombar, Vijay K.; Fraczkiewicz, Robert

doi:10.1007/978-1-4939-3609-0_4

Cited by 55 publications

(39 citation statements)

References 11 publications

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“…Theoretical plasma protein binding values were obtained from 2 sources used for log D 7.4 and pK a ; ACD/I‐Lab and ADMET Predictor (Simulations Plus) and 1 source available as a free online resource, PreADMET (version 2.0). These software packages are all commonly used for the prediction of physicochemical and pharmacokinetic parameters . Theoretical values were compared with experimental values by means of the absolute difference in values.…”

Section: Methodsmentioning

confidence: 99%

Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Manchester

Maskell

Waters

2018

Drug Testing and Analysis

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The misuse of benzodiazepines as new psychoactive substances is an increasing problem around the world. Basic physicochemical and pharmacokinetic data is required on these substances to interpret and predict their effects upon humans. Experimental log D , pK and plasma protein binding values were determined for 11 benzodiazepines that have recently appeared as new psychoactive substances (3-hydroxyphenazepam, 4'-chlorodiazepam, desalkylflurazepam, deschloroetizolam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, phenazepam, and pyrazolam) and compared with values generated by various software packages (ACD/I-lab, MarvinSketch, ADMET Predictor and PreADMET). ACD/I-LAB returned the most accurate values for log D and plasma protein binding while ADMET Predictor returned the most accurate values for pK . Large variations in predictive errors were observed between compounds. Experimental values are currently preferable and desirable as they may aid with the future 'training' of predictive models for these new psychoactive substances.

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Section: Methodsmentioning

confidence: 99%

Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Manchester

Maskell

Waters

2018

Drug Testing and Analysis

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“…Integrated systems were favored over less structured compendia of models such as ChemProp (http://www.ufz.de). More general and exhaustive tabulations of ADMET‐related software packages have been published recently elsewhere …”

Section: Introductionmentioning

confidence: 99%

Predicting mammalian metabolism and toxicity of pesticides in silico

Clark

2018

Pest Management Science

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Pesticides must be effective to be commercially viable but they must also be reasonably safe for those who manufacture them, apply them, or consume the food they are used to produce. Animal testing is key to ensuring safety, but it comes late in the agrochemical development process, is expensive, and requires relatively large amounts of material. Surrogate assays used as in vitro models require less material and shift identification of potential mammalian toxicity back to earlier stages in development. Modern in silico methods are cost‐effective complements to such in vitro models that make it possible to predict mammalian metabolism, toxicity and exposure for a pesticide, crop residue or other metabolite before it has been synthesized. Their broader use could substantially reduce the amount of time and effort wasted in pesticide development. This contribution reviews the kind of in silico models that are currently available for vetting ideas about what to synthesize and how to focus development efforts; the limitations of those models; and the practical considerations that have slowed development in the area. Detailed discussions are provided of how bacterial mutagenicity, human cytochrome P450 (CYP) metabolism, and bioavailability in humans and rats can be predicted. © 2018 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

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“…The C-terminal stretch sequence is formed by residues SYxxxEIxW indicated in Figure 4. Two Bartter syndrome associated KIR1.1 (Y314C; L320P) and two Andersen-Tawil syndrome associated KIR2.1 (delSY; W322S) confirmed trafficking mutations have been described in this region [46,48,54]. Interestingly, the W residue is not conserved in the KIR7.1 channel protein, which may indicate KIR subtype specific use of the entire Golgi-export signal motif.…”

Section: C-terminal Trafficking Mutation Hotspotmentioning

confidence: 94%

“…The Bartter syndrome associated loss-of-function A306T mutation in KIR1.1 is also located in the G-loop. Its expression in the Xenopus oocyte membrane is strongly reduced compared to wildtype channels [48]. At homologues positions, disease causing mutations have been found in KIR2.1 [49] and KIR6.2 [50] whose cause for loss-and gain-of-function, respectively, is unknown but may be caused by trafficking abnormalities.…”

Section: C-terminal Trafficking Mutation Hotspotmentioning

confidence: 99%

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Targeting Potassium Channel Trafficking in Cardiac Arrhythmia

Qile¹

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determines cardiac systolic/diastolic function, and abnormalities could result in cardiac arrhythmia and even sudden cardiac death (Hoffman and Cranefield, 1960).Chapter 1 2. Phase 1 is a phase of rapid repolarization beginning with rapid inactivation of voltage-gated Na + channels that aborts inward INa. At the same time, a transient outward K + current, Ito (Rudy, 2008), by activating voltage-gated K + channels briefly, leads to a slight negative shift of membrane potential (Santana et al., 2010; Grant, 2009). 3. Phase 2 is the plateau phase. The slow delayed rectifier K + current, IKs is slowly activated allowing K + efflux, which is partially balanced by the inward ICa,L activated at phase 0. Moreover, the increased concentration of intracellular Ca 2+ also activates Ca 2+ channels on the sarcoplasmic reticulum (SR), the so-called Ryanodine receptors, allowing Ca 2+ efflux move from SR to cytoplasm, a Ca 2+ activated Clcurrent (Hoffman, 1960) allowing Cl − into the cell, and ionic pumps like Na + -Ca 2+ exchanger and Na + -K + pump. All these ionic movements result in the membrane potential remaining almost constant with a low level of membrane repolarizing (Grant, 2009; Grunnet, 2010). 4. Phase 3 is the phase of rapid repolarization because L-type Ca 2+ channels close, while IKs remains activated and the negative change in membrane potential induces more K + currents, primarily the rapid delayed rectifier K + current (IKr) and the inward rectifier K + current (IK1). The strong outward K + current brings the membrane potential back to its resting value. The voltage-gated delayed rectifier K + channels close at ~-85 mV, while IK1 remains active and helps to maintain the resting membrane potential (Grant, 2009; Kubo et al., 2005). 5. Phase 4 represents the resting phase. The resting membrane potential is stable and more or less constant at ~-80 mV, resulting from perfect balance between influx of ions (e.g. Na + and Ca 2+ ) and efflux of ions (e.g. K + , Cland HCO3 -) (Santana, 2010; Morad and Tung, 1982). Among these ion channels, the potassium channel family is the largest branch. It can be broadly divided into two subfamilies by its transmembrane structure features: the six-transmembrane-helix voltage-gated potassium channel (Kv) and the two-transmembrane-helix inward rectifier potassium channel (KIR) (Ho et al., 1993).

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Modeling ADMET

Cited by 55 publications

References 11 publications

Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Predicting mammalian metabolism and toxicity of pesticides in silico

Targeting Potassium Channel Trafficking in Cardiac Arrhythmia

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Modeling ADMET

Cited by 55 publications

References 11 publications

Experimental versus theoretical log D7.4, pKa and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Experimental versus theoretical log D7.4, pKa and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Predicting mammalian metabolism and toxicity of pesticides in silico

Targeting Potassium Channel Trafficking in Cardiac Arrhythmia

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Product

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Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances