A BOILED‐Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules

Daina, Antoine; Zoete, Vincent

doi:10.1002/cmdc.201600182

Cited by 1,356 publications

(763 citation statements)

References 21 publications

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“…For assessing intestinal absorption, Caco-2 cell model categorizes compounds as low, middle and highly permeable corresponding to values <4 nm/sec, 4–70 nm/sec and >70 nm/sec respectively. SwissADME predicts BBB penetration and GI absorption by BOILED-Egg method [18]. It also classified compounds as targets of p-glycoprotein (p-gp) efflux, inhibitors of cytochrome P450 enzymes CYP2C9, CYP2C19, CYP2D6 and CYP3A4 and substrates for metabolism by CYP2D6 and CYP3A4.…”

Section: Methodsmentioning

confidence: 99%

Carboxylate derivatives of tributyltin (IV) complexes as anticancer and antileishmanial agents

et al. 2017

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BackgroundTributyltin (IV) compounds are promising candidates for drug development. In the current study, we evaluated in-vitro and in-silico profile of carboxylate derivatives of tributyltin (IV) complexes.MethodsADMET and drug-likeliness properties were predicted using MetaPrint2D React, preADMET, SwissADME and Molsoft tools. SwissTargetPrediction predicted molecular targets for compounds. In-vitro bioactivity was evaluated by quantifying cytotoxicity against HepG2, THP-1 cell lines, isolated lymphocytes and leishmania promastigotes as well as measuring protein kinase (PK) inhibition activity.ResultsResults indicate partial compliance of compounds with drug-likeliness rules. Ch-409 complies with WDI and Lipinski rules. ADMET profile prediction shows strong plasma protein binding except for Ch-409, low to high GI absorption and BBB penetration (Cbrain/Cblood = 0.942–11; caco-2 cells permeability 20.13–26.75 nm/sec), potential efflux by P-glycoprotein, metabolism by CYP3A4, medium inhibition of hERG, mutagenicity and capacity to be detoxified by glutathionation and glucuronidation. Molecular targets include proteases, enzymes, membrane receptors, transporters and ion channels where Ch-409 targets membrane receptors only. Compounds are significantly (p < 0.05) cytotoxic against HepG2 cell line and leishmania as compared with normal isolated lymphocytes. Ch-459 indicates highest toxicity against leishmania (mortality 97.9 ± 3.99%; LC50 0.323 ± 0.002 μg/mL) whereas Ch-409 possesses maximum cytotoxicity against HepG2 cell line (IC50 0.08 ± 0.001 μg/mL) as well as 97.5 ± 1.98% (LC50 0.954 ± 0.158 μg/mL) mortality of leishmania promastigotes. It was observed that antileishmanial effect was reduced by 16.38%–34.38% and 15–38.2% in the presence of NaN3 and mannitol respectively. PK inhibition and reactive oxygen species production are possible mechanisms for cytotoxicity.ConclusionsSelected carboxylate derivatives of tributyltin (IV) complexes possess significant antileishmanial and cytotoxic potential. These are promising compounds for the development of antileishmanial and anticancer drugs. Graphical AbstractCarboxylate derivatives of tributyltin (IV) complexes as anticancer and antileishmanial agents

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Section: Methodsmentioning

confidence: 99%

Carboxylate derivatives of tributyltin (IV) complexes as anticancer and antileishmanial agents

et al. 2017

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“…The protein and ligand were docked with iGEMDOCK and Autodock Vina [24], the results were retrieved on the basis of energy values, Van der Waals force, binding affinity between protein and ligand. The SAR molecules were generated with the help of SWISS ADME [25][26][27] online tool. In a study by Jeyam et al showed that a good interaction between 1,3 β glucan synthase with 20 phytoconstituents and the inhibition of 1,3 β glucan synthase was better than echinocandins [28].…”

Section: Discussionmentioning

confidence: 99%

Antifungal Activity of a Secondary Metabolite of Azadirachta Indica and Its Derivatives – An in Silico Study

Nagesh

Muniappan

Kannan

2018

Asian J Pharm Clin Res

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Objective: This study was aimed to inhibit the 1, 3 β-glucan synthase with azadirachtin or with the derivatives by docking method. Methods:The homology model of the protein 1, 3 β glucan synthase was prepared with "easy modellar" using query sequence and template and it was validated with procheck of Ramachandran plot. The ligand was selected from the PubChem database, and the .sdf file was downloaded which was converted to another file format with open babel. The .pdb files of protein and ligand were uploaded for rough docking with iGEMDOCK, and finally, the accurate docking was made with autodock vina. The docked poses were visualized with PYMOL then saved. The derivatives of the ligand were generated with SWISS ADME, free online software, and selected the derivative for docking. Results:The results obtained from iGEMDOCK and Autodock Vina were tabulated. It was found out that the Azadirachtin and the derivatives are effective in binding 1, 3 β Glucan synthase and thereby inhibiting the formation and integrity of fungal cell wall. Conclusion:In this study, the secondary metabolite Azadirachtin and the derivatives are showing inhibitory action against the model protein 1, 3 β glucan synthase and it was suggested that the external application of the ligand and its derivatives can be used because of their poor oral bioavailability.

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“…56 It computes the lipophilicity and hydrophilicity of the compounds and thus helps to determine whether the compounds are capable to be absorbed in the intestine or in the brain (Supporting Information). It was observed that all compounds except compound 2b were able to cross the blood brain barrier which had TPSA less than 90 A 2 .…”

Section: In Silico Adme Studiesmentioning

confidence: 99%

Green synthesis of enantiopure quinoxaline alcohols using Daucus carota

et al. 2019

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Green chemistry comprises a new approach in the synthesis of biologically active compounds using biocatalysts, thus diminishing the hazards for human health and environmental pollution. Asymmetric bioreduction is one of the most widely employed strategies in chemoenzymatic synthesis to produce enantiomerically pure chiral alcohols. The present study highlights the use biocatalyst Daucus carota for selective bioreduction of quinoxaline ketones 1a-6a to their corresponding optically pure alcohols 1b-6b in high yields (up to 84%) and good enantioselectivity (up to 98%). The absolute configuration of the chiral product (R)-1-(3-methyl 7-nitroquinoxalin-2-yl) ethan-1-ol 2b was confirmed by X-ray crystallography studies. The chiral R-configuration of the products obtained was confirmed by absolute configuration studies and was assigned following anti-Prelogs rule. Quinoxaline pharmacophores form a part of well-known potent drug molecules; hence, the chiral products were studied for determination of their molecular properties using SwissADME property analyser. All the chiral products show no Lipinski rule violations and are expected to have good oral bioavailability. As per the molecular properties prediction studies, the compound 6b (R)-1- (6,7-dichloro-3-methylquinoxalin-2-yl) ethanol is observed to show the best physicochemical properties to be a good lead molecule. Thus, the sustainable methodology was developed, and it confirms the synthesis of novel quinoxaline chiral alcohols in a simple, inexpensive, and eco-friendly condition using D carota.

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A BOILED‐Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules

Cited by 1,356 publications

References 21 publications

Carboxylate derivatives of tributyltin (IV) complexes as anticancer and antileishmanial agents

Carboxylate derivatives of tributyltin (IV) complexes as anticancer and antileishmanial agents

Antifungal Activity of a Secondary Metabolite of Azadirachta Indica and Its Derivatives – An in Silico Study

Green synthesis of enantiopure quinoxaline alcohols using Daucus carota

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