CypRules: a rule-based P450 inhibition prediction server

Shao, Chi-Yu; Su, Bo‐Han; Tu, Yi-Shu; Lin, Chun-Jung; Lin, Olivia A.; Tseng, Yufeng J.

doi:10.1093/bioinformatics/btv043

Cited by 34 publications

(23 citation statements)

References 9 publications

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“…The classifiers were trained on data from the PubChem Bioassay 1851 dataset (Veith et al., ) using 50 molecular and physicochemical descriptors. CypRules (Shao et al., ) is another web service that predicts inhibitors and non‐inhibitors of the same major CYPs based on the same data. It utilizes decision trees in combination with the concept of information entropy.…”

Section: Methods For Cyp Specificity Predictionmentioning

confidence: 99%

Computational methods and tools to predict cytochrome P450 metabolism for drug discovery

2019

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In this review, we present important, recent developments in the computational prediction of cytochrome P450 (CYP) metabolism in the context of drug discovery. We discuss in silico models for the various aspects of CYP metabolism prediction, including CYP substrate and inhibitor predictors, site of metabolism predictors (i.e., metabolically labile sites within potential substrates) and metabolite structure predictors. We summarize the different approaches taken by these models, such as rule‐based methods, machine learning, data mining, quantum chemical methods, molecular interaction fields, and docking. We highlight the scope and limitations of each method and discuss future implications for the field of metabolism prediction in drug discovery.

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Section: Methods For Cyp Specificity Predictionmentioning

confidence: 99%

Computational methods and tools to predict cytochrome P450 metabolism for drug discovery

2019

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“…Generally, to probe the molecular basis of CYP450 related metabolism, inhibition and drug–drug interaction potential a number of ligand-, structure-based and integrated modeling studies have been reported in literature [18,19,20,21,22,23,24,25]. Particularly, to gain deeper insights into the binding of ligands to CYP3A4, various in silico studies based on quantitative structure–activity relationships (QSAR), pharmacophore models and machine learning methods have been undertaken [26,27,28,29,30,31].…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors

Kiani

Ranaghan

Jabeen

et al. 2019

IJMS

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The Cytochrome P450 family of heme-containing proteins plays a major role in catalyzing phase I metabolic reactions, and the CYP3A4 subtype is responsible for the metabolism of many currently marketed drugs. Additionally, CYP3A4 has an inherent affinity for a broad spectrum of structurally diverse chemical entities, often leading to drug–drug interactions mediated by the inhibition or induction of the metabolic enzyme. The current study explores the binding of selected highly efficient CYP3A4 inhibitors by docking and molecular dynamics (MD) simulation protocols and their binding free energy calculated using the WaterSwap method. The results indicate the importance of binding pocket residues including Phe57, Arg105, Arg106, Ser119, Arg212, Phe213, Thr309, Ser312, Ala370, Arg372, Glu374, Gly481 and Leu483 for interaction with CYP3A4 inhibitors. The residue-wise decomposition of the binding free energy from the WaterSwap method revealed the importance of binding site residues Arg106 and Arg372 in the stabilization of all the selected CYP3A4-inhibitor complexes. The WaterSwap binding energies were further complemented with the MM(GB/PB)SA results and it was observed that the binding energies calculated by both methods do not differ significantly. Overall, our results could guide towards the use of multiple computational approaches to achieve a better understanding of CYP3A4 inhibition, subsequently leading to the design of highly specific and efficient new chemical entities with suitable ADMETox properties and reduced side effects.

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“…However, these in silico platforms have not been used to prospectively identify and biologically test new inhibitors. One of these platforms, CypRules 6 , is publicly available.…”

Section: Discussionmentioning

confidence: 99%

A combinatorial approach for the discovery of cytochrome P450 2D6 inhibitors from nature

Hochleitner

Akram

Ueberall

et al. 2017

Sci Rep

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The human cytochrome P450 2D6 (CYP2D6) enzyme is part of phase-I metabolism and metabolizes at least 20% of all clinically relevant drugs. Therefore, it is an important target for drug-drug interaction (DDI) studies. High-throughput screening (HTS) assays are commonly used tools to examine DDI, but show certain drawbacks with regard to their applicability to natural products. We propose an in silico – in vitro workflow for the reliable identification of natural products with CYP2D6 inhibitory potential. In order to identify candidates from natural product-based databases that share similar structural features with established inhibitors, a pharmacophore model was applied. The virtual hits were tested for the inhibition of recombinant human CYP2D6 in a bioluminescence-based assay. By controlling for unspecific interferences of the test compounds with the detection reaction, the number of false positives were reduced. The success rate of the reported workflow was 76%, as most of the candidates identified in the in silico approach were able to inhibit CYP2D6 activity. In summary, the workflow presented here is a suitable and cost-efficient strategy for the discovery of new CYP2D6 inhibitors with natural product libraries.

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CypRules: a rule-based P450 inhibition prediction server

Abstract: CypRules is freely accessible at http://cyprules.cmdm.tw/ and models, descriptor and program files for all compounds are publically available at http://cyprules.cmdm.tw/sources/sources.rar.

Cited by 34 publications

References 9 publications

Computational methods and tools to predict cytochrome P450 metabolism for drug discovery

Computational methods and tools to predict cytochrome P450 metabolism for drug discovery

Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors

A combinatorial approach for the discovery of cytochrome P450 2D6 inhibitors from nature

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