Estimation of alkane–water logP for neutral, acidic, and basic compounds using an alkylated polystyrene-divinylbenzene high-performance liquid chromatography column

Jensen, Derek A.; Gary, Ronald K.

doi:10.1016/j.chroma.2015.09.020

Cited by 7 publications

(3 citation statements)

References 56 publications

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“…Although the 1-octanol/water partition coefficient (log P oct ) − is a widely used design parameter in medicinal chemistry, it is unsuitable for characterization of aqueous solvation because 1-octanol can form HBs with solutes and log P oct does not sense HBDs in molecular structures. , The alkane/water partition coefficient (log P alk ) − is actually more suitable for assessing contributions of HBAs and HBDs to aqueous solvation. Water content at saturation for cyclohexane and hexadecane, the most commonly used solvents for log P alk measurement, is much lower than that of 1-octanol and partitioning , of charged forms of solutes into the organic solvent is also less of a concern than for 1-octanol.…”

Section: Partition Coefficientsmentioning

confidence: 99%

Hydrogen-Bond Donors in Drug Design

Kenny¹

2022

J. Med. Chem.

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Hydrogen-bond donors are seen to cause more problems for drug designers than hydrogen-bond acceptors. Most of the polarity in drug-like compounds comes from hydrogen-bond acceptors since they typically exceed the hydrogen-bond donors in number and are more heavily solvated on an individual basis. The implications of this polarity imbalance for optimization of permeability and aqueous solubility are discussed. A factor that should be considered in optimization of ligand recognition by targets is that the presence of a hydrogen-bond donor generally implies that a hydrogen-bond acceptor is also present (but not vice versa). Frustrated solvation and secondary electrostatic interactions result from aligned hydrogen-bond donors and acceptors, and the design opportunities presented by these phenomena are discussed. Hydrogen-bond donors based on oxygen, nitrogen and carbon are compared as target recognition elements, and halogen- and chalcogen-bond donors are discussed as hydrogen-bond donor equivalents.

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Section: Partition Coefficientsmentioning

confidence: 99%

Hydrogen-Bond Donors in Drug Design

Kenny¹

2022

J. Med. Chem.

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“…Although the 1-octanol/water partition coefficient (logPoct) [49][50][51] is a widely used design parameter in medicinal chemistry, it is unsuitable for characterization of aqueous solvation because 1-octanol can form HBs with solutes and logPoct does not sense HBDs in molecular structures [52,53]. The alkane/water partition coefficient (logPalk) [54][55][56][57][58][59][60][61][62][63][64][65][66] is actually more suitable for assessing contributions of HBAs and HBDs to aqueous solvation. Water content at saturation for cyclohexane and hexadecane, the most commonly used solvents for logPalk measurement, is much lower than that of 1-octanol [67] and partitioning [68,69] of charged forms of solutes into the organic solvent is also less of a concern than for 1-octanol.…”

Section: Hydrogen Bond Aciditymentioning

confidence: 99%

Hydrogen bond donors in drug design

Kenny¹

2022

Preprint

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In medicinal chemistry, hydrogen bond donors are seen to cause more problems than hydrogen bond acceptors and this study examines hydrogen bond donor-acceptor asymmetries in the context of drug design. Hydrogen bond acidity is reviewed and it is shown how polarity can be estimated for individual hydrogen bond donors and acceptors from alkane/water partition coefficient measurements. Hydrogen bond donors are generally less polar than hydrogen bond acceptors and desolvation penalty is therefore an implausible explanation for deleterious effects of hydrogen bond donors. Generally, the number of hydrogen bond acceptors in organic compounds exceeds the number of hydrogen bond donors and the apparently greater restrictiveness of the Rule of 5 for hydrogen bond donors may simply be a reflection of this imbalance. The weaker hydration of hydrogen bond donors implies that attempts to address polarity surfeit in optimization of permeability should be focused on hydrogen bond acceptors. Elimination of redundant hydrogen bond donors can potentially reduce active efflux and destabilize the solid state without resulting in unacceptable increases in lipophilicity. The key hydrogen bond donor-acceptor asymmetry in the context of target recognition is that the presence of a hydrogen bond donor usually implies that a hydrogen bond acceptor is also present. Target-ligand hydrogen bonds form in aqueous media and design opportunities presented by frustrated hydration and secondary interactions are discussed. Hydrogen bond donors based on oxygen, nitrogen and carbon are compared as target recognition elements and potential benefits of halogen and chalcogen bond donors as replacements for hydrogen bond donors are discussed.

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“…For instance, ElogD is a widely accepted RP-HPLC method for log D oct determination; furthermore, EPSA is a Supercritical Fluid Chromatography (SFC) method describing exposed polarity of the molecule in low dielectric constant environment. A few studies have been published over the years suggesting that the polymeric columns − could be useful for characterization of drug candidates.…”

Section: Introductionmentioning

confidence: 99%

A Fast Chromatographic Method for Estimating Lipophilicity and Ionization in Nonpolar Membrane-Like Environment

et al. 2016

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This study describes the design and implementation of a new chromatographic descriptor called log k'80 PLRP-S that provides information about the lipophilicity of drug molecules in the nonpolar environment, both in their neutral and ionized form. The log k'80 PLRP-S obtained on a polymeric column with acetonitrile/water mobile phase is shown to closely relate to log Ptoluene (toluene dielectric constant ε ∼ 2). The main intermolecular interactions governing log k'80 PLRP-S were deconvoluted using the Block Relevance (BR) analysis. The information provided by this descriptor was compared to ElogD and calclog Ptol, and the differences are highlighted. The "charge-flush" concept is introduced to describe the sensitivity of log k'80 PLRP-S to the ionization state of compounds in the pH range 2 to 12. The ability of log k'80 PLRP-S to indicate the propensity of neutral molecules and monoanions to form Intramolecular Hydrogen Bonds (IMHBs) is proven through a number of examples.

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Estimation of alkane–water logP for neutral, acidic, and basic compounds using an alkylated polystyrene-divinylbenzene high-performance liquid chromatography column

Cited by 7 publications

References 56 publications

Hydrogen-Bond Donors in Drug Design

Hydrogen-Bond Donors in Drug Design

Hydrogen bond donors in drug design

A Fast Chromatographic Method for Estimating Lipophilicity and Ionization in Nonpolar Membrane-Like Environment

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