Matched Molecular Pairs as a Medicinal Chemistry Tool

Griffen, Ed; Leach, Andrew G.; Robb, Graeme R.; Warner, Daniel J.

doi:10.1021/jm200452d

Cited by 261 publications

(270 citation statements)

References 59 publications

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“…To a certain extent, proposed methodology could be considered as somewhat similar to matched molecular pairs approach (MMPA) [47][48][49] in application to QSAR field. The difference between the property of two related structures, e.g., A-B and A-C, containing the common fragment A is explained by the difference in the structure of fragments B and C. To estimate the influence of B to C transformation, in MMPA one can calculate the difference between observed property values for compounds A-B and A-C or between predicted property values by corresponding QSAR models.…”

Section: Universal Approach For Structural Interpretation Of Qsar Modelsmentioning

confidence: 99%

Universal Approach for Structural Interpretation of QSAR/QSPR Models

Polishchuk

Кузьмин

Artemenko

et al. 2013

Molecular Informatics

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In this paper we offer a novel approach for the structural interpretation of QSAR models. The major advantage of our developed methodology is its universality, i.e., it can be applied to any QSAR/QSPR model irrespective of chemical descriptors and machine learning methods applied. This universality was achieved by using only the information obtained from substructures of the compounds of interest to interpret model outcomes. Reliability of the offered approach was confirmed by the results of three case studies, including end-points of different types (continuous and binary classification) and nature (solubility, mutagenicity, and inhibition of Transglutaminase 2), various fragment and whole-molecule descriptors (Simplex and Dragon), and multiple modeling techniques (partial least squares, random forest, and support vector machines). We compared the global contributions of molecular fragments obtained using our methodology with known SAR rules derived experimentally. In all cases high concordance between our interpretation and results published by others was observed. Although the proposed interpretation approach could be easily extended to any type of descriptors, we would recommend using Simplex descriptors to achieve a larger variety of investigated molecular fragments. The developed approach is a good tool for interpretation of such "black box" models like random forest, neural networks, etc. Analysis of fragment global contributions and their deviation across a dataset could be useful for the identification of key fragments and structural alerts. This information could be helpful to maximize the positive influence of structural surroundings on the given fragment and to decrease the negative effects.

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Section: Universal Approach For Structural Interpretation Of Qsar Modelsmentioning

confidence: 99%

Universal Approach for Structural Interpretation of QSAR/QSPR Models

Polishchuk

Кузьмин

Artemenko

et al. 2013

Molecular Informatics

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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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“…While a variety of similarity measures are applicable, our preferred similarity criterion for ACs is the formation of transformation size-restricted matched molecular pairs (tsr-MMPs) [4]. An MMP is defined as a pair of compounds that are only distinguished by a structural change at a single site [5], corresponding to the exchange of two substructures, termed a (chemical) transformation [6]. Transformation size restrictions are applied to limit MMP compounds to typical analogs from medicinal chemistry [4].…”

Section: Activity Cliffsmentioning

confidence: 99%

From Activity Cliffs to Promiscuity Cliffs

Bajorath

2017

Future Sci. OA

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Matched Molecular Pairs as a Medicinal Chemistry Tool

Cited by 261 publications

References 59 publications

Universal Approach for Structural Interpretation of QSAR/QSPR Models

Universal Approach for Structural Interpretation of QSAR/QSPR Models

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

From Activity Cliffs to Promiscuity Cliffs

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