Two‐ and three‐dimensional QSAR of carrier‐mediated transport of β‐lactam antibiotics in Caco‐2 cells

Wanchana, Suchada; Yamashita, Fumiyoshi; Hara, H.; Fujiwara, Sayaka; Akamatsu, Miki; Hashida, Mitsuru

doi:10.1002/jps.20220

Cited by 18 publications

(10 citation statements)

References 31 publications

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“…Our estimates suggest that the concentration of EF‐1α in the leishmania translation systems can go as high as ∼1 μ M (see Materials and Methods), while some studies in the literature report cellular concentration of EF‐1α, being as high as 30–60 μ M 34. Furthermore, these complex extracts are more likely to contain numerous cellular components capable of interacting nonspecifically with the tested compounds (this is a very common drug bioavailability issue39–42). Both of these factors are likely to reduce the magnitude of observed inhibition and imply that antileishmanial potencies of NSC36398, NSC122281, and particularly NSC4347 are actually higher.…”

Section: Resultsmentioning

confidence: 99%

Indel‐based targeting of essential proteins in human pathogens that have close host orthologue(s): Discovery of selective inhibitors for Leishmania donovani elongation factor‐1α

et al. 2007

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We propose a novel strategy for selective targeting of essential pathogen proteins that contain sizable indels (insertions/deletions) in their sequences compared with their host orthologues. This approach has been tested on elongation factor-1alpha (EF-1alpha) from the protozoan pathogen Leishmania donovani. Leishmania EF-1alpha is 82% identical to the corresponding human orthologue, but possesses a 12 aminoacid sequence deletion compared with human EF-1alpha. We used this indel-differentiated region to design small molecules that selectively bind to leishmania EF-1alpha and not to the human protein. Three unrelated molecules were identified with the capacity to inhibit protein synthesis in leishmania by up to 75% while exhibiting no effect on human protein translation. These candidates may serve as prototypes for future development of antiprotozoan therapeutics. More generally, these findings provide a basis for a novel drug design platform. This platform targets essential pathogen proteins that are highly conserved across species, and consequently would not typically be considered to be conventional drug targets. We anticipate that such indel-directed targeting of essential proteins in microbial pathogens may help address the growing problem of antibiotic resistance.

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Section: Resultsmentioning

confidence: 99%

Indel‐based targeting of essential proteins in human pathogens that have close host orthologue(s): Discovery of selective inhibitors for Leishmania donovani elongation factor‐1α

et al. 2007

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“…These authors performed two-and three-dimensional QSAR of uptake rates of 20 b-lactam antibiotics into Caco-2 cells we had published in 1999 (Bretschneider et al 1999). The authors concluded that the simple 2D-QSAR approach gives a sufficient predictability of uptake (Wanchana et al 2004).…”

Section: Molecular Modelling Of Pept1 and Pept2 Substratesmentioning

confidence: 99%

“…Hence, the model can only predict affinity, not transport. Such a prediction of transport rates has been attempted by Wanchana et al (2004). These authors performed two-and three-dimensional QSAR of uptake rates of 20 b-lactam antibiotics into Caco-2 cells we had published in 1999 (Bretschneider et al 1999).…”

Section: Molecular Modelling Of Pept1 and Pept2 Substratesmentioning

confidence: 99%

Pharmaceutical and pharmacological importance of peptide transporters

Brandsch

Knütter

Bosse-Doenecke

2008

Journal of Pharmacy and Pharmacology

197

188

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Peptide transport is currently a prominent topic in membrane research. The transport proteins involved are under intense investigation because of their physiological importance in protein absorption and also because peptide transporters are possible vehicles for drug delivery. Moreover, in many tissues peptide carriers transduce peptidic signals across membranes that are relevant in information processing. The focus of this review is on the pharmaceutical relevance of the human peptide transporters PEPT1 and PEPT2. In addition to their physiological substrates, both carriers transport many beta-lactam antibiotics, valaciclovir and other drugs and prodrugs because of their sterical resemblance to di- and tripeptides. The primary structure, tissue distribution and substrate specificity of PEPT1 and PEPT2 have been well characterized. However, there is a dearth of knowledge on the substrate binding sites and the three-dimensional structure of these proteins. Until this pivotal information becomes available by X-ray crystallography, the development of new drug substrates relies on classical transport studies combined with molecular modelling. In more than thirty years of research, data on the interaction of well over 700 di- and tripeptides, amino acid and peptide derivatives, drugs and prodrugs with peptide transporters have been gathered. The aim of this review is to put the reports on peptide transporter-mediated drug uptake into perspective. We also review the current knowledge on pharmacogenomics and clinical relevance of human peptide transporters. Finally, the reader's attention is drawn to other known or proposed human peptide-transporting proteins.

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“…In addition, a very important advantage of this new approach is that the derivation of 3D structures for the compounds in the training set is not necessary, which was critical in previously used Structure -Activity Relationships (SAR) strategies, as well as time-consuming. To our knowledge, the only article not dealing directly with structural features that are important for PEPT1 transport, like in the article of Gebauer and co-workers, but rather with descriptors derived from those structural features, is the article by Wanchana et al [22]. The authors calculated a total of 220 connectivity, shape and atom-type E-state indices to model the cellular uptake of 20 b-lactams with PLS.…”

Section: Discussionmentioning

confidence: 98%

A performance evaluation of multiple classification models of human PEPT1 inhibitors and non‐inhibitors

2007

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The human PEPT1 protein is an influx transporter known to influence the ADME profile of several bioactive compounds. A good example is acyclovir, which possesses high safety and selectivity but has a low bioavailability. The l-valyl ester prodrug of this compound is transported by PEPT1, resulting in a three-to four-fold increase in plasma levels. Therefore, knowledge of the Structure -Activity Relationships (SAR) of PEPT1 ligands can enable us to favourably manipulate the ADME properties of promising leads that suffer from low bioavailability. We applied three classification methods (naïve Bayesian classification, recursive partitioning and linear discriminant analysis) together with the descriptors best suited for each method to a large PEPT1 inhibitor/non-inhibitor dataset. This dataset was assembled from literature and was divided into three groups: the inhibitor group (K i 1 mM, 113 compounds), the unknown group (K i > 1 mM and < 4.48 mM, 21 compounds) and the non-inhibitor group (K i ! 4.48 mM, 69 compounds). The inhibitor and non-inhibitor groups were used to build the models. The Bayesian classification model together with fingerprint descriptors was found to produce the best results. Of a test set of 46 compounds, it correctly classified 89% (concordance). It correctly classified 96% of the inhibitors and 78% of the non-inhibitors. Although the model informs us only about structural requirements for inhibition and not necessarily for transportation, the SAR identified by the Bayesian model support previously published results. In addition, the results were obtained in a short-time span, without the need of three-dimensional configurations and with more compounds than in previous studies.

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Two‐ and three‐dimensional QSAR of carrier‐mediated transport of β‐lactam antibiotics in Caco‐2 cells

Cited by 18 publications

References 31 publications

Indel‐based targeting of essential proteins in human pathogens that have close host orthologue(s): Discovery of selective inhibitors for Leishmania donovani elongation factor‐1α

Indel‐based targeting of essential proteins in human pathogens that have close host orthologue(s): Discovery of selective inhibitors for Leishmania donovani elongation factor‐1α

Pharmaceutical and pharmacological importance of peptide transporters

A performance evaluation of multiple classification models of human PEPT1 inhibitors and non‐inhibitors

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