chemalot and chemalot_knime: Command line programs as workflow tools for drug discovery

Lee, Man-Ling; Aliagas, Ignacio; Feng, Jianwen; Gabriel, Thomas R.; O'Donnell, TJ; Sellers, Benjamin D.; Wiswedel, Bernd; Gobbi, A.

doi:10.1186/s13321-017-0228-9

Cited by 19 publications

(12 citation statements)

References 18 publications

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“…Analysis of the Physicochemical Properties. Calculated physicochemical properties were derived using Genentech internal computational chemistry suite; 19 the distribution of the calculated properties with respect to MDR1 mediated efflux and gMDCKI permeability were analyzed and plotted using the default R function and the package ggpubr and ggplot. 20 ■ RESULTS CRISPR-Cas9-Mediated Canine Mdr1 Knockout in MDCKI Wildtype Cells.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Evaluating the Utility of Canine Mdr1 Knockout Madin-Darby Canine Kidney I Cells in Permeability Screening and Efflux Substrate Determination

Chen¹,

Broccatelli²,

Plise³

et al. 2018

Mol. Pharmaceutics

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Permeability assays are commonly conducted with Madin-Darby canine kidney (MDCK) cells to predict the intestinal absorption of small-molecule drug candidates. In addition, MDCK cells transfected to overexpress efflux transporters are often used to identify substrates. However, MDCK cells exhibit endogenous efflux activity for a significant proportion of experimental compounds, potentially leading to the underestimation of permeability and confounded findings in transport studies. The goal of this study was to evaluate canine Mdr1 knockout MDCK (gMDCKI) cells in permeability screening and human MDR1 substrate determination in a drug discovery setting. The gMDCKI cells were established by CRISPR-Cas9-mediated knockout of the canine Mdr1 gene in MDCKI wildtype (wt) cells. A comparison of efflux ratios (ER) between MDCKI wt and gMDCKI showed that out of 135 compounds tested, 38% showed efflux activity in MDCKI wt, while no significant efflux was observed in gMDCKI cells. Apparent permeability (Papp) from apical-to-basolateral (A-to-B) and basolateral-to-apical were near unity in gMDCKI cells, which approximated passive permeability, and 17% of compounds demonstrated increases in their Papp A-to-B values. Overexpression of human MDR1 in gMDCKI (gMDCKI-MDR1) cells enabled substrate determination without the contribution of endogenous efflux, and the assay was able to deconvolute ambiguous results from MDCKI-MDR1 and identify species differences in substrate specificity. An analysis of 395 and 474 compounds in gMDCKI and gMDCKI-MDR1, respectively, suggested physicochemical properties that were associated with low permeability correlated with MDR1 recognition. Poorly permeable compounds and MDR1 substrates were more likely to be large, flexible, and more capable of forming external hydrogen bonds. On the basis of our evaluation, we concluded that gMDCKI is a better cell line for permeability screening and efflux substrate determination than the MDCK wt cell line.

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Section: ■ Materials and Methodsmentioning

confidence: 99%

Evaluating the Utility of Canine Mdr1 Knockout Madin-Darby Canine Kidney I Cells in Permeability Screening and Efflux Substrate Determination

Chen¹,

Broccatelli²,

Plise³

et al. 2018

Mol. Pharmaceutics

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“…Molecular modeling studies were performed using MOE (Chemical Computing Group ULC, 2018) with the MMFF94x forcefield (Halgren, 1996d;Halgren, 1996b;Halgren, 1996a;Halgren, 1996c;Halgren and Nachbar, 1996;Halgren, 1999b;Halgren, 1999a) and docking was performed with Glide (Schrödinger LLC, 2016). Conformational analyses of the dimer structures were performed with the sdfMMConfAnalysis module of the Chemalot software package (Lee et al, 2017).…”

Section: Molecular Modelingmentioning

confidence: 99%

Novel Homodimer Metabolites of GDC-0994 via Cytochrome P450–Catalyzed Radical Coupling

Takahashi¹,

Grandner²,

Bobba³

et al. 2020

Drug Metabolism and Disposition

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Two novel homodimer metabolites were identified in rat samples collected during the in vivo study of GDC-0994. In this study, we investigated the mechanism of the formation of these metabolites. We generated and isolated the dimer metabolites using a biomimetic oxidation system for NMR structure elucidation to identify a symmetric dimer formed via carbon-carbon bond between two pyrazoles, and an asymmetric dimer formed via an aminopyrazole-nitrogen to pyrazole-carbon bond. In vitro experiments demonstrated formation of these dimers was catalyzed by cytochrome P450 enzymes with CYP3A4/5 being the most efficient. Using Density Functional Theory (DFT), we determined these metabolites share a mechanism of formation, initiated by an N-H hydrogen atom abstraction by the catalytically active iron-oxo of CYPs. Molecular modeling studies also show these dimer metabolites fit in the CYP3A4 binding site in low energy conformations with minimal protein rearrangement. Collectively, the results of these experiments suggest that formation of these two homodimer metabolites is mediated by CYP3A, likely involving activation of two GDC-0994 molecules by a single P450 enzyme and proceeding through a radical coupling mechanism.

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“…We as a community can address this by broadening our understanding of what “reproducing” a cheminformatics study means. Advances in methodology are best evaluated by independent reimplementation of the algorithm as described in detail by the original authors in step-by-step text or pseudocode [5–7]. The Journal should support such endeavors, particularly where an original publication is not completely transparent because of commercial or proprietary considerations, especially where neither source code nor scripts were part of the original report.…”

Section: Commentarymentioning

confidence: 99%

A path to next-generation reproducibility in cheminformatics

Clark

2019

J Cheminform

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Currently, the submission guidelines for the Journal of Cheminformatics say it will “only publish research or software that is entirely reproducible by third parties.” They go on to specify that being reproducible means that anything essential to the conclusion of the paper be freely accessible and states that source code must be provided. I submit that this definition of reproducibility is too narrow—that a cheminformatics method can only truly be replicated by reimplementing it from a detailed, step-by-step high-level description to determine how reliably the algorithm per se does what it is intended to do.

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chemalot and chemalot_knime: Command line programs as workflow tools for drug discovery

Cited by 19 publications

References 18 publications

Evaluating the Utility of Canine Mdr1 Knockout Madin-Darby Canine Kidney I Cells in Permeability Screening and Efflux Substrate Determination

Evaluating the Utility of Canine Mdr1 Knockout Madin-Darby Canine Kidney I Cells in Permeability Screening and Efflux Substrate Determination

Novel Homodimer Metabolites of GDC-0994 via Cytochrome P450–Catalyzed Radical Coupling

A path to next-generation reproducibility in cheminformatics

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