In Silico Assessment of ADME Properties: Advances in Caco-2 Cell Monolayer Permeability Modeling

Pham-The, Hai; Cabrera‐Pérez, Miguel Ángel; Nam, Nguyen Hai; Castillo-Garit, Juan A.; Rasulev, Bakhtiyor; Le-Thi-Thu, Huong; Casañola-Martín, Gerardo M.

doi:10.2174/1568026619666181130140350

Cited by 49 publications

(26 citation statements)

References 134 publications

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“…Finally, we also predicted the passive transmembrane permeation using Caco-2 cell monolayers or MDCK cells as models. Currently, both models are used as a simplified in vitro model for intestinal absorption in drug development (Broccatelli et al, 2016;Pham-The et al, 2018;Press & Di Grandi, 2008). Our results showed that in comparison with reference drugs, Speciophylline, Uncarine F and Uncaric acid have 72-342 nm/s.…”

Section: Ligandmentioning

confidence: 78%

Uncaria tomentosa(cat’s claw): a promising herbal medicine against SARS-CoV-2/ACE-2 junction and SARS-CoV-2 spike protein based on molecular modeling

Yepes-Pérez

Herrera-Calderon

Quintero‐Saumeth

2020

Journal of Biomolecular Structure and Dynamics

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COVID-19 is a novel severe acute respiratory syndrome coronavirus. Currently, there is no effective treatment and vaccines seem to be the solution in the future. Virtual screening of potential drugs against the S protein of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) has provided small molecular compounds with a high binding affinity. Unfortunately, most of these drugs do not attach with the binding interface of the receptor-binding domain (RBD)-angiotensin-converting enzyme-2 (ACE-2) complex in host cells. Molecular modeling was carried out to evaluate the potential antiviral properties of the components of the medicinal herb Uncaria tomentosa (cat's claw) focusing on the binding interface of the RBD-ACE-2 and the viral spike protein. The in silico approach starts with protein-ligand docking of 26 Cat's claw key components followed by molecular dynamics simulations and re-docked calculations. Finally, we carried out drug-likeness calculations for the most qualified cat's claw components. The structural bioinformatics approaches led to the identification of several bioactive compounds of U. tomentosa with potential therapeutic effect by dual strong interaction with interface of the RBD-ACE-2 and the ACE-2 binding site on SARS-CoV-2 RBD viral spike. In addition, in silico drug-likeness indices for these components were calculated and showed good predicted therapeutic profiles of these phytochemicals found in U. tomentosa (cat's claw). Our findings suggest the potential effectiveness of cat's claw as complementary and/or alternative medicine for COVID-19 treatment.

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Section: Ligandmentioning

confidence: 78%

Uncaria tomentosa(cat’s claw): a promising herbal medicine against SARS-CoV-2/ACE-2 junction and SARS-CoV-2 spike protein based on molecular modeling

Yepes-Pérez

Herrera-Calderon

Quintero‐Saumeth

2020

Journal of Biomolecular Structure and Dynamics

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“…The QikProp software allowed further predictions on pharmacokinetic properties of 4 and 5, based on similarities with those of the 95% of a dataset of known drugs and drug-like compounds, e.g. predicted blockade of hERG K + channels, 31 predicted Caco-2 monolayer permeability, 32 and predicted MDCK monolayer permeability. 33,34 These preliminary predictions (data not shown) indicated that, at therapeutic concentrations, 4 might be expected to cross to the blood-brain barrier via passive diffusion.…”

Section: Drug-likeness Of 4 Andmentioning

confidence: 99%

Flavones as tyrosinase inhibitors: kinetic studies in vitro and in silico

Arroo

Sarı

Barut

et al. 2020

Phytochemical Analysis

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Introduction Tyrosinase is a multifunctional copper‐containing oxidase enzyme that catalyses the first steps in the formation of melanin pigments. Identification of tyrosinase inhibitors is of value for applications in cosmetics, medicine and agriculture. Objective To develop an analytical method that allows identification of drug‐like natural products that can be further developed as tyrosinase inhibitors. Results of in vitro and in silico studies will be compared in order to gain a deeper insight into the mechanism of action of enzyme inhibition. Method Using an in vitro assay we tested tyrosinase inhibitor effects of five structurally related flavones, i.e. luteolin (1), eupafolin (2), genkwanin (3), nobiletin (4), and chrysosplenetin (5). The strongest inhibitors were further investigated in silico, using enzyme docking simulations. Results All compounds tested showed modest tyrosinase inhibitory effect compared to the positive control, kojic acid. The polymethoxy flavones 4 and 5 exhibited the strongest tyrosinase inhibitory effect with the half maximal inhibitory concentration (IC50) values of 131.92 ± 1.75 μM and 99.87 ± 2.38 μM respectively. According to kinetic analysis 2, 4 and 5 were competitive inhibitors, whereas 1 and 3 were non‐competitive inhibitors of tyrosinase. Docking studies indicated that methoxy groups on 4 and 5 caused steric hindrance which prevented alternative binding modes in the tyrosinase; the methoxy groups on the B‐ring of these flavones faced the catalytic site in the enzyme. Conclusions The docking simulations nicely complemented the in vitro kinetic studies, opening the way for the development of predictive models for use in drug design.

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“…MDCK (nm/s) [h] 316 86 87 % GI [i] 95 Furthermore, hybrid 1 could exhibit a greater human oral gastrointestinal (GI) absorption about 95 %, which may suggest that the small molecule could be absorbed throughout the intestinal segments upon oral administration. To support this data, calculated permeation through Caco-2 cell monolayers or MDCK cells [50][51][52] may also indicate a good permeation for this compound inside the gut epithelial wall, displaying optimal values of 662 and 316 nm/s. In accordance with reference values taken from 95 % of FDA-approved drugs together with that ideal range for lipid-based formulations (À 2.0 to 6.0), [53] 1 could have an optimal lipophilicity value (logP o/w ) of 3.050, which may suggest the ability of the molecule to penetrate the lipid bilayers of the infected cells.…”

Section: In-silico Pharmacokinetic Analysis (Physicochemical and Admementioning

confidence: 84%

Biologically Active Quinoline‐Hydrazone Conjugates as Potential Trypanosoma cruzi DHFR‐TS Inhibitors: Docking, Molecular Dynamics, MM/PBSA and Drug‐Likeness Studies

2021

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Chagas disease, is a chronic parasitic infection caused by protozoan parasites belonging to the genus Trypanosoma. New therapies for Chagas infections are urgently needed and represent a major challenge in medicinal chemistry. As part of these efforts, we recently designed and synthesized a series of molecular hybrids bearing quinoline and hydrazones moieties, with some of them displaying higher anti‐trypanosomal activities than benznidazole. Thus, the current work is focused on proposing a plausible action mechanism by which the most active compounds inhibited T. cruzi growth based on multilevel computational approaches. Docking showed that for the best binders there was a marked preference for binding to dihydrofolate reductase (DHFR) over cruzipain (around −9.0 kcal/mol). MD simulations not only validate the reliability of docking predictions, but showed that the ligand‐receptor complex was stable during the extended 50 ns simulations inside the active site (RMSD value of 1.96±0.34 Å). Furthermore, MM/PBSA studies also affirm the docking results. The MM/PBSA method revealed that most of the residues involved in the binding event are hydrophobic in nature, which are in accordance with those aminoacids essential in the DHFR function. Satisfactory pharmacokinetics profiles were also estimated for the top‐three active compounds. Finally, the results suggested that the active hybrids might act by inhibiting DHFR activity within T. cruzi, making them a privileged scaffold that can be used in future anti‐Chagas drug development.

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In Silico Assessment of ADME Properties: Advances in Caco-2 Cell Monolayer Permeability Modeling

Cited by 49 publications

References 134 publications

Uncaria tomentosa(cat’s claw): a promising herbal medicine against SARS-CoV-2/ACE-2 junction and SARS-CoV-2 spike protein based on molecular modeling

Uncaria tomentosa(cat’s claw): a promising herbal medicine against SARS-CoV-2/ACE-2 junction and SARS-CoV-2 spike protein based on molecular modeling

Flavones as tyrosinase inhibitors: kinetic studies in vitro and in silico

Biologically Active Quinoline‐Hydrazone Conjugates as Potential Trypanosoma cruzi DHFR‐TS Inhibitors: Docking, Molecular Dynamics, MM/PBSA and Drug‐Likeness Studies

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