Leveraging chromatography based physicochemical properties for efficient drug design

Goetz, Gilles H.; Shalaeva, Marina

doi:10.5599/admet.529

Cited by 21 publications

(20 citation statements)

References 76 publications

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“…The internal chemical diversity for both datasets was quantified by calculating the nearest‐neighbour similarity using Tanimoto coefficient together with MACCS and Morgan2‐fingerprints (see Supporting Information S2). As pointed out by Goetz and Shalaeva, industrial drug discovery teams usually work with limited number of different chemical series in projects and this is also seen here as both internal MACCS‐ and Morgan2‐similarities are higher in the Orion dataset. This can be also observed from the clusters seen in Principal Components Analysis (PCA) on MACCS fingerprints (Figure ).…”

Section: Methodsmentioning

confidence: 66%

“…In this study, we were interested in the off‐the‐shelf performance of commercially available pK a models and the use of data fusion in order to improve their accuracy. It should be stressed that it has been well established that pK a predictions as well as predictions of other related constants such as logD on internal datasets can be dramatically improved by re‐training the models using the mispredicted molecules and sometimes even a single training compound from the novel chemical space is enough to make the model perform adequately …”

Section: Resultsmentioning

confidence: 99%

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Predicting pK_a for Small Molecules on Public and In‐house Datasets Using Fast Prediction Methods Combined with Data Fusion

Kalliokoski

Sinervo

2019

Molecular Informatics

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Data fusion approach was investigated in the context of pK a prediction for 391 small molecules derived from a public data source as well as for 681 compounds from an internal corporate database. Four different pKa prediction methods (Simulations Plus ADMET-Predictor S + pKa, ACD/Labs Percepta Classic, ACD/Labs Percepta GALAS and Epik) were used to predict the most acidic or basic pKa for each of the compounds. By using data fusion, the median absolute error for the internal compounds was reduced from the best performing single model's value of 0.69 down to 0.50. In addition to the improved accuracy, data fusion also enabled predictions for all of the compounds in the dataset as individual methods failed on some of the molecules.

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Section: Methodsmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Predicting pK_a for Small Molecules on Public and In‐house Datasets Using Fast Prediction Methods Combined with Data Fusion

Kalliokoski

Sinervo

2019

Molecular Informatics

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“…The lipophilicity of molecules represents their affinity for a lipophilic environment, and the lipophilicity may be expressed as log P [ 55 , 56 ]. The molecular polar surface area (PSA) is a very useful parameter for the prediction of drug transport properties, and PSA is defined as a sum of the surfaces of polar atoms [ 57 ].…”

Section: Resultsmentioning

confidence: 99%

Pleiotropic Properties of Amphiphilic Dihydropyridines, Dihydropyridones, and Aminovinylcarbonyl Compounds

Ruciņš

Smits

Sipola

et al. 2020

Oxidative Medicine and Cellular Longevity

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Three groups of synthetic lipids are chosen for studies: (1) 1,4-dihydropyridines (1,4-DHPs) containing two cationic moieties and their analogues; (2) 3,4-dihydro-2(1H)-pyridones containing a cationic moiety; and (3) acyclic, open-chain analogues, i.e., 2-amino-3-alkoxycarbonylalkylammonium derivatives. 1,4-DHPs possessing dodecyl alkyl chains in the ester groups in positions 3 and 5 and cationic nitrogen-containing groups in positions 2 and 6 have high cytotoxicity in cancer cells HT-1080 (human lung fibrosarcoma) and MH-22A (mouse hepatoma), but low cytotoxicity in the noncancerous NIH3T3 cells (mouse embryonic fibroblast). On the contrary, similar compounds having short (methyl, ethyl, or propoxyethyl) chains in the ester groups in positions 3 and 5 lack cytotoxicity in the cancer cells HT-1080 and MH-22A even at high doses. Inclusion of fluorine atoms in the alkyl chains in positions 3 and 5 of the DHP cycle decreases the cytotoxicity of the mentioned compounds. Structurally related dihydropyridones with a polar head group are substantially more toxic to normal and cancerous cells than the DHP analogues. Open-chain analogues of DHP lipids comprise the same conjugated aminovinylcarbonyl moiety and possess anticancer activity, but they also have high basal cytotoxicity. Electrochemical oxidation data demonstrate that oxidation potentials of selected compounds are in the range of 1.6–1.7 V for cationic 1,4-DHP, 2.0–2.4 V for cationic 3,4-dihydropyridones, and 1.2–1.5 V for 2-amino-3-alkoxycarbonylalkylammonium derivatives. Furthermore, the tested cationic 1,4-DHP amphiphiles possess antiradical activity. Molecular topological polar surface area values for the tested compounds were defined in accordance with the main fragments of compound structures. The determined log P values were highest for dodecyl ester groups in positions 3 and 5 of the 1,4-DHP and lowest for short alkyl chain-containing amphiphiles.

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“…Lipophilicity is one of the most frequently examined physicochemical properties of drug candidates. Typically, it is determined in order to support quantitative structure-activity relationships (QSAR), including prediction of biological process such as absorption, tissue distribution, and others pharmacokinetic properties [1,2]. Moreover, lipophilicity is also taken into account in lipophilic ligand efficiency assessments (LLE) [1,3].…”

Section: Introductionmentioning

confidence: 99%

Lipophilicity Determination of Quaternary (Fluoro)Quinolones by Chromatographic and Theoretical Approaches

Ciura

Fedorowicz

Andrić

et al. 2019

IJMS

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Lipophilicity is a vital physicochemical parameter of a molecule, which affects several biological processes such as absorption, tissue distribution, and pharmacokinetic properties. In this study, evaluation of lipophilicities of a series of novel fluoroquinolone-Safirinium dye hybrids using chromatographic and computational methods is presented. Fluoroquinolone-Safirinium dye hybrids have been synthesized as new dual-acting hydrophilic antibacterial agents. Reversed phase thin-layer chromatography and micellar electrokinetic chromatography experiments were carried out. Furthermore, logP values of the target structures were predicted by means of different software platforms and algorithms. In order to assess similarities and dissimilarities of the obtained lipophilicity indexes, cluster analysis and sum of ranking differences were performed. The significant differences of calculated logP values (α = 0.05, p < 0.001) indicated that an experimental approach is necessary for lipophilicity prediction of this class of antibiotics. Chromatographic data indicated that the newly synthesized hybrid (fluoro)quinolone-based quaternary ammonium derivatives show less lipophilic character than the parent (fluoro)quinolones. Additionally, the chromatographically obtained lipophilicity indexes were evaluated for possible application in quantitative retention–activity relationships. The established lipophilicity models have the potential to predict antimicrobial activities of a series of quaternary (fluoro)quinolones against Bacillus subtilis, Escherichia coli, and Proteus vulgaris.

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Leveraging chromatography based physicochemical properties for efficient drug design

Cited by 21 publications

References 76 publications

Predicting pK_a for Small Molecules on Public and In‐house Datasets Using Fast Prediction Methods Combined with Data Fusion

Predicting pK_a for Small Molecules on Public and In‐house Datasets Using Fast Prediction Methods Combined with Data Fusion

Pleiotropic Properties of Amphiphilic Dihydropyridines, Dihydropyridones, and Aminovinylcarbonyl Compounds

Lipophilicity Determination of Quaternary (Fluoro)Quinolones by Chromatographic and Theoretical Approaches

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Leveraging chromatography based physicochemical properties for efficient drug design

Cited by 21 publications

References 76 publications

Predicting pKa for Small Molecules on Public and In‐house Datasets Using Fast Prediction Methods Combined with Data Fusion

Predicting pKa for Small Molecules on Public and In‐house Datasets Using Fast Prediction Methods Combined with Data Fusion

Pleiotropic Properties of Amphiphilic Dihydropyridines, Dihydropyridones, and Aminovinylcarbonyl Compounds

Lipophilicity Determination of Quaternary (Fluoro)Quinolones by Chromatographic and Theoretical Approaches

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Product

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Predicting pK_a for Small Molecules on Public and In‐house Datasets Using Fast Prediction Methods Combined with Data Fusion

Predicting pK_a for Small Molecules on Public and In‐house Datasets Using Fast Prediction Methods Combined with Data Fusion