Computational prediction of octanol–water partition coefficient based on the extended solvent-contact model

Kim, Sang Woo; Park, Hwangseo

doi:10.1016/j.jmgm.2015.06.004

Cited by 17 publications

(5 citation statements)

References 23 publications

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“…The logPo/w is a crucial pharmacokinetic determinant, which affects membrane permeability, metabolism, binding potency to the target, bioavailability and toxicity of compounds [ 49 ]. In order to show its physiological effect, compounds should also transport to the site of action in particular in aqueous environments as the human body consists of approximately 60% water.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

et al. 2022

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Plants have paved the way for the attainment of molecules with a wide-range of biological activities. However, plant products occasionally show low biological activities and/or poor pharmacokinetic properties. In that case, development of their derivatives as drugs from the plant world has been actively performed. As plant products, plastoquinones (PQs) have been of high importance in anticancer drug design and discovery; we have previously evaluated and reported the potential cytotoxic effects of a series of PQ analogs. Among these analogs, PQ2, PQ3 and PQ10 were selected for National Cancer Institute (NCI) for in vitro screening of anticancer activity against a wide range of cancer cell lines. The apparent superior anticancer potency of PQ2 on the HCT-116 colorectal cancer cell line than that of PQ3 and PQ10 compared to other tested cell lines has encouraged us to perform further mechanistic studies to enlighten the mode of anti-colorectal cancer action of PQ2. For this purpose, its apoptotic effects on the HCT-116 cell line, DNA binding capacity and several crucial pharmacokinetic properties were investigated. Initially, MTT assay was conducted for PQ2 at different concentrations against HCT-116 cells. Results indicated that PQ2 exhibited significant cytotoxicity in HCT-116 cells with an IC50 value of 4.97 ± 1.93 μM compared to cisplatin (IC50 = 26.65 ± 7.85 μM). Moreover, apoptotic effects of PQ2 on HCT-116 cells were investigated by the annexin V/ethidium homodimer III staining method and PQ2 significantly induced apoptosis in HCT-116 cells compared to cisplatin. Based on the potent DNA cleavage capacity of PQ2, molecular docking studies were conducted in the minor groove of the double helix of DNA and PQ2 presented a key hydrogen bonding through its methoxy moiety. Overall, both in vitro and in silico studies indicated that effective, orally bioavailable drug-like PQ2 attracted attention for colorectal cancer treatment. The most important point to emerge from this study is that appropriate derivatization of a plant product leads to unique biologically active compounds.

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

et al. 2022

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“…There is a large body of work related to measurement or prediction of log k OW based on, for instance, quantitative structure–property relationships (QSPRs). , Although efforts into developing better experimental methods are ongoing, more research is focused on computational predictions ranging from coarse-grained simulations to analytical reference interaction site model theory, to quantum chemistry, to machine learning , and other empirical methods. , Interestingly, log k OW have been used to parameterize models for dissipative particle dynamics simulations as well . Simultaneously, there are still new efforts to measure new physicochemical data including log k OW with improvement of QSPR methods being one of the reasons .…”

Section: Introductionmentioning

confidence: 99%

Prediction of Partition Coefficients of Environmental Toxins Using Computational Chemistry Methods

et al. 2019

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The partitioning of compounds between aqueous and other phases is important for predicting toxicity. Although thousands of octanol–water partition coefficients have been measured, these represent only a small fraction of the anthropogenic compounds present in the environment. The octanol phase is often taken to be a mimic of the inner parts of phospholipid membranes. However, the core of such membranes is typically more hydrophobic than octanol, and other partition coefficients with other compounds may give complementary information. Although a number of (cheap) empirical methods exist to compute octanol–water (log k OW ) and hexadecane–water (log k HW ) partition coefficients, it would be interesting to know whether physics-based models can predict these crucial values more accurately. Here, we have computed log k OW and log k HW for 133 compounds from seven different pollutant categories as well as a control group using the solvation model based on electronic density (SMD) protocol based on Hartree–Fock (HF) or density functional theory (DFT) and the COSMO-RS method. For comparison, XlogP3 (log k OW ) values were retrieved from the PubChem database, and KowWin log k OW values were determined as well. For 24 of these compounds, log k OW was computed using potential of mean force (PMF) calculations based on classical molecular dynamics simulations. A comparison of the accuracy of the methods shows that COSMO-RS, KowWin, and XlogP3 all have a root-mean-square deviation (rmsd) from the experimental data of ≈0.4 log units, whereas the SMD protocol has an rmsd of 1.0 log units using HF and 0.9 using DFT. PMF calculations yield the poorest accuracy (rmsd = 1.1 log units). Thirty-six out of 133 calculations are for compounds without known log k OW , and for these, we provide what we consider a robust prediction, in the sense that there are few outliers, by averaging over the methods. The results supplied may be instrumental when developing new methods in computational ecotoxicity. The log k HW values are found to be strongly correlated to log k OW for most compounds.

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“…Lipophilicity is measured through the n -octanol/water partition coefficient, LOGP. The implicit log P method uses implicit solvation models to calculate the solvation free energy through a combination of generalized Born and solvent accessible surface area methodologies and has been shown to exhibit strong predictive power when compared to similar approaches and control molecules [ 112 , 113 ]. In a recent study, several potential drugs for the treatment of SARS-CoV-2 were analyzed with the use of the SwissADME database, reporting iLOGP as a parameter for determining if the molecules adhered to Lipinski’s rule of five [ 114 ].…”

Section: Resultsmentioning

confidence: 99%

An investigation of binding interactions of tumor-targeted peptide conjugated polyphenols with the kinase domain of ephrin B4 and B2 receptors

et al. 2023

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Recent studies have shown that Ephrin receptors may be upregulated in several types of cancers including breast, ovarian and endometrial cancers, making them a target for drug design. In this work, we have utilized a target-hopping approach to design new natural product-peptide conjugates and examined their interactions with the kinase-binding domain of EphB4 and EphB2 receptors. The peptide sequences were generated through point mutations of the known EphB4 antagonist peptide TNYLFSPNGPIA. Their anticancer properties and secondary structures were analyzed computationally. Conjugates of most optimum of peptides were then designed by binding the N-terminal of the peptides with the free carboxyl group of the polyphenols sinapate, gallate and coumarate, which are known for their inherent anticancer properties. To investigate if these conjugates have a potential to bind to the kinase domain, we carried out docking studies and MMGBSA free energy calculations of the trajectories based on the molecular dynamics simulations, with both the apo and the ATP bound kinase domains of both receptors. In most cases binding interactions occurred within the catalytic loop region, while in some cases the conjugates were found to spread out across the N-lobe and the DFG motif region. The conjugates were further tested for prediction of pharmacokinetic properties using ADME studies. Our results indicated that the conjugates were lipophilic and MDCK permeable with no CYP interactions. These findings provide an insight into the molecular interactions of these peptides and conjugates with the kinase domain of the EphB4 and EphB2 receptor. As a proof of concept, we synthesized and carried out SPR analysis with two of the conjugates (gallate-TNYLFSPNGPIA and sinapate-TNYLFSPNGPIA). Results indicated that the conjugates showed higher binding with the EphB4 receptor and minimal binding to EphB2 receptor. Sinapate-TNYLFSPNGPIA showed inhibitory activity against EphB4. These studies reveal that some of the conjugates may be developed for further investigation into in vitro and in vivo studies and potential development as therapeutics. Graphic Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11030-023-10621-x.

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Computational prediction of octanol–water partition coefficient based on the extended solvent-contact model

Cited by 17 publications

References 23 publications

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

Prediction of Partition Coefficients of Environmental Toxins Using Computational Chemistry Methods

An investigation of binding interactions of tumor-targeted peptide conjugated polyphenols with the kinase domain of ephrin B4 and B2 receptors

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