WizePairZ: a novel algorithm to identify, encode, and exploit matched molecular pairs with unspecified cores in medicinal chemistry

Warner, Daniel J.; St-Gallay, Stephen A.; Griffen, Edward J.

doi:10.1186/1758-2946-3-s1-o9

Cited by 24 publications

(41 citation statements)

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“…Matched molecular pairs analysis (Griffen et al, 2011) was performed on the full set of 624 compounds using the WizePairZ algorithm (Warner et al, 2010). To deconvolute the intrinsic effects of structural transformations from their associated effect on molecular properties, two variables were considered in the analysis: BSEP activity, expressed as Ϫlog 10 (IC 50 ) (or pIC 50 ) and ClogP.…”

Section: Inhibition Of Human Bile Salt Export Pump By Drugsmentioning

confidence: 99%

Mitigating the Inhibition of Human Bile Salt Export Pump by Drugs: Opportunities Provided by Physicochemical Property Modulation, In Silico Modeling, and Structural Modification

et al. 2012

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ABSTRACT:The human bile salt export pump (BSEP) is a membrane protein expressed on the canalicular plasma membrane domain of hepatocytes, which mediates active transport of unconjugated and conjugated bile salts from liver cells into bile. BSEP activity therefore plays an important role in bile flow. In humans, genetically inherited defects in BSEP expression or activity cause cholestatic liver injury, and many drugs that cause cholestatic drug-induced liver injury (DILI) in humans have been shown to inhibit BSEP activity in vitro and in vivo. These findings suggest that inhibition of BSEP activity by drugs could be one of the mechanisms that initiate human DILI. To gain insight into the chemical features responsible for BSEP inhibition, we have used a recently described in vitro membrane vesicle BSEP inhibition assay to quantify transporter inhibition for a set of 624 compounds. The relationship between BSEP inhibition and molecular physicochemical properties was investigated, and our results show that lipophilicity and molecular size are significantly correlated with BSEP inhibition. This data set was further used to build predictive BSEP classification models through multiple quantitative structure-activity relationship modeling approaches. The highest level of predictive accuracy was provided by a support vector machine model (accuracy ‫؍‬ 0.87, ‫؍‬ 0.74). These analyses highlight the potential value that can be gained by combining computational methods with experimental efforts in early stages of drug discovery projects to minimize the propensity of drug candidates to inhibit BSEP.

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Section: Inhibition Of Human Bile Salt Export Pump By Drugsmentioning

confidence: 99%

Mitigating the Inhibition of Human Bile Salt Export Pump by Drugs: Opportunities Provided by Physicochemical Property Modulation, In Silico Modeling, and Structural Modification

et al. 2012

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“…15 This provides an implementation of the MCSS pair finding algorithm described by Warner et al and of the F+I method described by Hussain and Rea. 13,14 The MCSS identified in MCpairs is limited to contiguous atoms (no disconnected substructures are identified). The structural change linking pairs of molecules is encoded by SMIRKS and these are modified to include differing levels of chemical context.…”

Section: Methodsmentioning

confidence: 99%

“…[30][31][32] The data that were obtained in the preparation of the SALT database were used to identify improved ways to analyze the matched pairs output. In this case, the pairs were identified using the MCSS approach with settings as described by Warner et al 13 The number of experimental results included in the MMPA and the resulting number of unique structural transformations that were identified in each set of data is given in Table S1 in the supporting information. "hERG" refers to block of the hERG-encoded potassium ion channel, reported as a pIC 50 .…”

Section: Methodsmentioning

confidence: 99%

Turbocharging Matched Molecular Pair Analysis: Optimizing the Identification and Analysis of Pairs

Lukac

Zarnecka

Griffen³

et al. 2017

J. Chem. Inf. Model.

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We have applied the two most commonly used methods for automatic matched pair identification, obtained the optimum settings, and discovered that the two methods are synergistic. A turbocharging approach to matched pair analysis is advocated in which a first round (a conservative categorical approach that uses an analogy with coin flips, heads corresponding to an increase in a measured property, tails to a decrease, and a biased coin to a structural change that reliably causes a change in that property) provides the settings for a second round (which uses the magnitude of the change in properties). Increased chemical specificity allows reliable knowledge to be extracted from smaller sets of pairs, and an assay-specific upper limit can be placed on the number of pairs required before adequate sampling of variability has been achieved.

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“…101 WizePairZ is a system developed at AstraZeneca that uses maximum common subgraph searching to identify MMPs. 102 The MUDO (MolecUle eDitOr) tool can automatically generate new structures by applying molecular transformations (such as those derived from MMPA) to structures. A variation of the MMPA approach was described by Sheridan et al, 103 in which pairs of compounds are described by transformation vectors (the difference vector for a pair of molecular fingerprints).…”

Section: Matched Molecular Pair Analysismentioning

confidence: 99%

Modern 2D QSAR for drug discovery

Lewis

Wood

2014

WIREs Comput Mol Sci

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2D QSAR is a powerful tool for explaining the relationships between chemical structure and experimental observations. Key elements of the method are the numerical descriptors used to translate a chemical structure into mathematical variables, the quality of the observed data and the statistical methods used to derive the relationships between the observations and the descriptors. There are some caveats to what is essentially a simple procedure: overfitting of the data, domain applicability to new structures and making good error estimates for each prediction. 2D QSAR models are used routinely during the process of optimization of a chemical series towards a candidate for clinical trials. As more knowledge is gained in this area, 2D QSARs will become acceptable surrogates for experimental observations. WIREs Comput Mol Sci 2014, 4:505–522. doi: 10.1002/wcms.1187 This article is categorized under: Structure and Mechanism > Molecular Structures Computer and Information Science > Chemoinformatics

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WizePairZ: a novel algorithm to identify, encode, and exploit matched molecular pairs with unspecified cores in medicinal chemistry

Cited by 24 publications

References 0 publications

Mitigating the Inhibition of Human Bile Salt Export Pump by Drugs: Opportunities Provided by Physicochemical Property Modulation, In Silico Modeling, and Structural Modification

Mitigating the Inhibition of Human Bile Salt Export Pump by Drugs: Opportunities Provided by Physicochemical Property Modulation, In Silico Modeling, and Structural Modification

Turbocharging Matched Molecular Pair Analysis: Optimizing the Identification and Analysis of Pairs

Modern 2D QSAR for drug discovery

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