Characterization of the hydrophobic properties of amino acids on the basis of their partition and distribution coefficients in the 1-octanol-water system

Chmelı́k, Josef; Hudeček, Jiřı́; Putyera, Karol; Makovička, Jiří; Kalous, V.; Chmelíková, Jitka

doi:10.1135/cccc19912030

Cited by 18 publications

(19 citation statements)

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“…LogD7.4 values of -0.70 and 1.11 were measured for [ 18 F]FPG and [ 18 F]FBPG, respectively. These values are much higher than the -3.64 logD7.4 value reported for glutamine32 . This is explained by the introduction of the lipophilic side-chain to the glutamine.…”

contrasting

confidence: 60%

Radiosynthesis,in vitroand preliminaryin vivoevaluation of the novel glutamine derived PET tracers [¹⁸F]fluorophenylglutamine and [¹⁸F]fluorobiphenylglutamine

Baguet

Verhoeven

Pauwelyn

et al. 2020

Preprint

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AbstractIntroductionGlucose has been deemed the driving force of tumor growth for decades. However, research has shown that several tumors metabolically shift towards glutaminolysis. The development of radiolabeled glutamine derivatives could be a useful molecular imaging tool for visualizing these tumors. We elaborated on the glutamine-derived PET tracers by developing two novel probes, namely [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamineMaterials and methodsBoth tracers were labelled with fluorine-18 using our recently reported ruthenium-based direct aromatic fluorination method. Their affinity was evaluated with a [3H]glutamine inhibition experiment in a human PC-3 and a rat F98 cell line. The imaging potential of [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine was tested using a mouse PC-3 and a rat F98 tumor model.ResultsThe radiosynthesis of both tracers was successful with overall non-decay corrected yields of 18.46 ± 4.18 % (n=10) ([18F]fluorophenylglutamine) and 8.05 ± 3.25 % (n=5) ([18F]fluorobiphenylglutamine). In vitro inhibition experiments showed a moderate and low affinity of fluorophenylglutamine and fluorobiphenylglutamine, respectively, towards the human ASCT-2 transporter. Both compounds had a low affinity towards the rat ASCT-2 transporter. These results were endorsed by the in vivo experiments with low uptake of both tracers in the F98 rat xenograft, low uptake of [18F]FBPG in the mice PC-3 xenograft and a moderate uptake of [18F]FPG in the PC-3 tumors.ConclusionWe investigated the imaging potential of two novel PET radiotracers [18F]FPG and [18F]FBPG. [18F]FPG is the first example of a glutamine radiotracer derivatized with a phenyl group which enables the exploration of further derivatization of the phenyl group to increase the affinity and imaging qualities. We hypothesize that increasing the affinity of [18F]FPG by optimizing the substituents of the arene ring can result in a high-quality glutamine-based PET radiotracer.Advances in Knowledge and Implications for patient careWe hereby report novel glutamine-based PET-tracers. These tracers are tagged on the arene group with fluorine-18, hereby preventing in vivo defluorination, which can occur with alkyl labelled tracers (e.g. (2S,4R)4-[18F]fluoroglutamine). [18F]FPG shows clear tumor uptake in vivo, has no in vivo defluorination and has a straightforward production. We believe this tracer is a good starting point for the development of a high-quality tracer which is useful for the clinical visualization of the glutamine transport.

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confidence: 60%

Radiosynthesis,in vitroand preliminaryin vivoevaluation of the novel glutamine derived PET tracers [¹⁸F]fluorophenylglutamine and [¹⁸F]fluorobiphenylglutamine

Baguet

Verhoeven

Pauwelyn

et al. 2020

Preprint

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“…To validate the computational measurement of wettability of amino acid side chains on the basis of the artificial planar peptide networks, we compare the hydrophobicity data obtained from our simulations to previously reported hydrophobicity scales of amino acid residues, which include the experimental free energies of transfer relative to glycine (13) (Fig. 5A), computed free energies based on accessible surface areas (30) (Fig. 5B), conditional solvation free energies based on empirical force-field model (18) (Fig.…”

Section: Significancementioning

confidence: 98%

Characterizing hydrophobicity of amino acid side chains in a protein environment via measuring contact angle of a water nanodroplet on planar peptide network

Zhu

Gao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

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Hydrophobicity of macroscopic planar surface is conventionally characterized by the contact angle of water droplets. However, this engineering measurement cannot be directly extended to surfaces of proteins, due to the nanometer scale of amino acids and inherent nonplanar structures. To measure the hydrophobicity of side chains of proteins quantitatively, numerous parameters were developed to characterize behavior of hydrophobic solvation. However, consistency among these parameters is not always apparent. Herein, we demonstrate an alternative way of characterizing hydrophobicity of amino acid side chains in a protein environment by constructing a monolayer of amino acids (i.e., artificial planar peptide network) according to the primary and the β-sheet secondary structures of protein so that the conventional engineering measurement of the contact angle of a water droplet can be brought to bear. Using molecular dynamics simulations, contact angles θ of a water nanodroplet on the planar peptide network, together with excess chemical potentials of purely repulsive methane-sized Weeks−Chandler−Andersen solute, are computed. All of the 20 types of amino acids and the corresponding planar peptide networks are studied. Expectedly, all of the planar peptide networks with nonpolar amino acids are hydrophobic due to θ > 90°, whereas all of the planar peptide networks of the polar and charged amino acids are hydrophilic due to θ < 90°. Planar peptide networks of the charged amino acids exhibit complete-wetting behavior due to θ = 0°. This computational approach for characterization of hydrophobicity can be extended to artificial planar networks of other soft matter.hydrophobicity | amino acids | contact angle | nanodroplet | water H ydrophobic effect on the microscopic level can be understood via analysis of unfavorable ordering of water molecules around nonpolar solutes, where dynamic hydrogen bonds among water molecules nearby can be disrupted (1). The hydrophobic interaction is well known as one of the major driving forces for protein folding, and is also a key factor to stabilize the globular or binding structures of single protein, multiprotein, and protein−ligand systems (2-5). According to previous studies, the hydrophobicity of proteins can be attributed mainly to the side chains of amino acid residues, which are the structural units of protein backbones (5-7). Hence, quantitative characterization of the hydrophobicity of amino acids in protein environment is crucial to our understanding of the protein functionalities in biological environment and also to the prediction of synthetic peptide structures.Over the past three decades, extensive studies have been devoted to understanding hydrophobic interaction and hydrophobic hydration on the molecular levels (8-37). However, the quantitative description of the hydrophobicity of protein and amino acid residues still largely hinges on molecular thermodynamic properties of the residues rather the structural properties of the protein polymer itself. In engineering fields,...

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“…Today almost every practicing pharmaceutical scientist knows the difference between log P and log D [239][240][241][242][243][244][245][246]. Better understanding of the partitioning behavior of ampholytes and charged species emerged [247][248][249][250][251][252][253][254][255][256][257][258][259][260][261]. The concept of the micro-log P was formalized [195,212,242,244].…”

Section: Partitioning Into Octanolmentioning

confidence: 99%

Physicochemical Profiling (Solubility, Permeability and Charge State)

Avdeef¹

2004

Frontiers in Medicinal Chemistry - Online

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About 30% of drug candidate molecules are rejected due to pharmacokineticrelated failures. When poor pharmaceutical properties are discovered in development, the costs of bringing a potent but poorly absorbable molecule to a product stage by "formulation" can become very high. Fast and reliable in vitro prediction strategies are needed to filter out problematic molecules at the earliest stages of discovery. This review will consider recent developments in physicochemical profiling used to identify candidate molecules with physical properties related to good oral absorption. Poor solubility and poor permeability account for many PK failures. FDA's Biopharmaceutics Classification System (BCS) is an attempt to rationalize the critical components related to oral absorption. The core idea in the BCS is an in vitro transport model, centrally embracing permeability and solubility, with qualifications related to pH and dissolution. The objective of the BCS is to predict in vivo performance of drug products from in vitro measurements of permeability and solubility. In principle, the framework of the BCS could serve the interests of the earliest stages of discovery research. The BCS can be rationalized by considering Fick's first law, applied to membranes. When molecules are introduced on one side of a lipid membrane barrier (e.g., epithelial cell wall) and no such molecules are on the other side, passive diffusion will drive the molecules across the membrane. When certain simplifying assumptions are made, the flux equation in Fick's law reduces simply to a product of permeability and solubility. Many other measurable properties are closely related to permeability and solubility. Permeability (P e) is a kinetic parameter related to lipophilicity (as indicated by the partition and distribution coefficients, log P and log D). Retention (R) of lipophilic molecules by the membrane (which is related to lipophilicity and may predict PK volumes of distribution) influences the characterization of permeability. Furthermore, strong drug interactions with serum proteins can influence permeability. The unstirred water layer on both sides of the membrane barrier can impose limits on permeability. Solubility (S) is a thermodynamic parameter, and is closely related to dissolution, a kinetic parameter. The unstirred water layer on the surfaces of suspended solids imposes limits on dissolution. Bile acids effect both solubility and dissolution, by a micellization effect. For ionizable molecules, pH plays a crucial role. The charge state that a molecule exhibits at a particular pH is characterized by the ionization constant (pK a) of the molecule. Buffers effect pH gradients in the unstirred water layers, which can dramatically affect both permeability and dissolution of ionizable molecules. In this review, we will focus on the emerging instrumental methods for the measurement of the physicochemical parameters P e, S, pKa, R, log P, and log D (and their pH-profiles). These physicochemical profiles can be valuable tools for the medicinal che...

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Characterization of the hydrophobic properties of amino acids on the basis of their partition and distribution coefficients in the 1-octanol-water system

Cited by 18 publications

References 0 publications

Radiosynthesis,in vitroand preliminaryin vivoevaluation of the novel glutamine derived PET tracers [¹⁸F]fluorophenylglutamine and [¹⁸F]fluorobiphenylglutamine

Radiosynthesis,in vitroand preliminaryin vivoevaluation of the novel glutamine derived PET tracers [¹⁸F]fluorophenylglutamine and [¹⁸F]fluorobiphenylglutamine

Characterizing hydrophobicity of amino acid side chains in a protein environment via measuring contact angle of a water nanodroplet on planar peptide network

Physicochemical Profiling (Solubility, Permeability and Charge State)

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Characterization of the hydrophobic properties of amino acids on the basis of their partition and distribution coefficients in the 1-octanol-water system

Cited by 18 publications

References 0 publications

Radiosynthesis,in vitroand preliminaryin vivoevaluation of the novel glutamine derived PET tracers [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine

Radiosynthesis,in vitroand preliminaryin vivoevaluation of the novel glutamine derived PET tracers [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine

Characterizing hydrophobicity of amino acid side chains in a protein environment via measuring contact angle of a water nanodroplet on planar peptide network

Physicochemical Profiling (Solubility, Permeability and Charge State)

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Product

Resources

About

Radiosynthesis,in vitroand preliminaryin vivoevaluation of the novel glutamine derived PET tracers [¹⁸F]fluorophenylglutamine and [¹⁸F]fluorobiphenylglutamine

Radiosynthesis,in vitroand preliminaryin vivoevaluation of the novel glutamine derived PET tracers [¹⁸F]fluorophenylglutamine and [¹⁸F]fluorobiphenylglutamine