Stereoselective binding of chiral ligands to single nucleotide polymorphisms of the human organic cation transporter-1 determined using cellular membrane affinity chromatography

Moaddel, Ruin; Bighi, F; Yamaguchi, Rika; Patel, Sharvil; Ravichandran, Sarangan; Wainer, Irving W.

doi:10.1016/j.ab.2010.02.034

Cited by 7 publications

(3 citation statements)

References 13 publications

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“…It is possible that subjects with these polymorphisms may have different levels of single nucleotide polymorphisms (SNP) expression level and cellular localization and, consequently, varying degrees of efflux capability to model compounds [51]. Further studies are needed to determine which level and sites of SNP mainly contribute to the specificity of BCRP bindings.…”

Section: Resultsmentioning

confidence: 99%

Computational analysis and predictive modeling of polymorph descriptors

Lee

Jana

Acharya

et al. 2013

Chemistry Central Journal

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BackgroundA computation approach based on integrating high throughput binding affinity comparison and binding descriptor classifications was utilized to establish the correlation among substrate properties and their affinity to Breast Cancer Resistant Protein (BCRP). The uptake rates of Mitoxantrone in the presence of various substrates were evaluated as an in vitro screening index for comparison of their binding affinity to BCRP.The effects of chemical properties of various chemotherapeutics, such as antiviral, antibiotic, calcium channel blockers, anticancer and antifungal agents, on their affinity to BCRP, were evaluated using HEK (human embryonic kidney) cells in which 3 polymorphs, namely 482R (wild type) and two mutants (482G and 482T) of BCRP, have been identified. The quantitative structure activity relationship (QSAR) model was developed using the sequential approaches of Austin Model 1 (AM1), CODESSA program, heuristic method (HM) and multiple linear regression (MLR) to establish the relationship between structural specificity of BCRP substrates and their uptake rates by BCRP polymorphs.ResultsThe BCRP mutations may induce conformational changes as manifested by the altered uptake rates of Mitoxantrone by BCRP in the presence of other competitive binding substrates that have a varying degree of affinities toward BCRP efflux. This study also revealed that the binding affinity of test substrates to each polymorph was affected by varying descriptors, such as constitutional, topological, geometrical, electrostatic, thermodynamic, and quantum chemical descriptors.ConclusionDescriptors involved with the net surface charge and energy level of substrates seem to be the common integral factors for defining binding specificity of selected substrates to BCRP polymorph. The reproducible outcomes and validation process further supported the accuracy of the computational model in assessing the correlation among descriptors involved with substrate affinity to BCRP polymorph. A quantitative computation approach will provide important structural insight into optimal designing of new chemotherapeutic agents with improved pharmacological efficacies.

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Section: Resultsmentioning

confidence: 99%

Computational analysis and predictive modeling of polymorph descriptors

Lee

Jana

Acharya

et al. 2013

Chemistry Central Journal

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“…42 A large number of transmembrane proteins have been immobilized using this method including GPCRs: cannabinoid receptors, 43 P2Y1 purinergic receptor, 44 LGICs: α3β4, α3β4α5, α4β2, α4β4, α7 nicotinic receptors, 45–47 g-amino-butyric acid receptors and N -methyl-D-aspartate receptors; 41 ATP binding cassette (ABC) transporters: Pgp, BCRP, MRP1; 48,49 and Solute Carrier transmembrane proteins including OAT, OCT1, OCT1R488M and OCT1G465R. 50–52 …”

Section: Identification Of Bioactive Componentsmentioning

confidence: 99%

“…42 A large number of transmembrane proteins have been immobilized using this method including GPCRs: cannabinoid receptors, 43 P2Y1 purinergic receptor, 44 LGICs: a3b4, a3b4a5, a4b2, a4b4, a7 nicotinic receptors, [45][46][47] g-amino-butyric acid receptors and N-methyl-Daspartate receptors; 41 ATP binding cassette (ABC) transporters: Pgp, BCRP, MRP1; 48,49 and Solute Carrier transmembrane proteins including OAT, OCT1, OCT1R488M and OCT1G465R. [50][51][52] In cellular membrane chromatography (CMC), cell membranes are suspended in buffer and ruptured by ultrasonic procedure. 53 The resulting homogenate is centrifuged at low speed to remove nuclei followed by high speed centrifugation to yield cell membranes.…”

Section: Cellular Membrane Affinity Chromatographymentioning

confidence: 99%

Comparison of analytical techniques for the identification of bioactive compounds from natural products

2016

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Natural product extracts are a rich source of bioactive compounds. As a result, the screening of natural products for the identification of novel biologically active metabolites has been an essential part of several drug discovery programs. It is estimated that more than 70% of all drugs approved from 1981 and 2006, were either derived from or structurally similar to nature based compounds indicating the necessity for the development of a rapid method for the identification of novel compounds from plant extracts. The screening of biological matrices for the identification of novel modulators is nevertheless still challenging. In this review we discuss current techniques in phytochemical analysis and the identification of biologically active components.

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