The significance of acid/base properties in drug discovery

Manallack, David T.; Prankerd, Richard J.; Yuriev, Elizabeth; Oprea, Tudor I.; Chalmers, David K.

doi:10.1039/c2cs35348b

Cited by 268 publications

(260 citation statements)

References 59 publications

(153 reference statements)

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“…Consideration of acidbase properties in conjunction with other molecular properties is of great significance and has the potential to be used to further improve the efficiency of drug discovery. Acid-base properties also play a very significant role in the formulation of a drug substance for both oral and intravenous dosage forms [8].…”

Section: Introductionmentioning

confidence: 99%

Advances in microspeciation of drugs and biomolecules: Species-specific concentrations, acid-base properties and related parameters

Mazák

Noszál

2016

Journal of Pharmaceutical and Biomedical Analysis

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Section: Introductionmentioning

confidence: 99%

Advances in microspeciation of drugs and biomolecules: Species-specific concentrations, acid-base properties and related parameters

Mazák

Noszál

2016

Journal of Pharmaceutical and Biomedical Analysis

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“…In general; carboxylic acid moieties can have detrimental effects on the volume of distribution [33]. Incidentally there are specific enzymes as evidenced by the short half-life for anti-inflammatory drugs.…”

Section: Squaryl Molecular Metaphorsmentioning

confidence: 99%

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Kitson¹

2017

J Diagn Imaging Ther

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Molecular Metaphors is the application of squaryl building blocks towards creative functional group chemistry to produce lead compounds and imaging agents. This strategy is applied to rational drug design and to various imaging agents that would normally contain conventional functional group chemistry. These, include carboxylic acids, α-amino acids, peptide bonds and phosphonates. Moreover, the squaryl metaphor is a precursor to complex organic molecules involving functional group interchange (FGI) and rearrangements. This article discusses the application of these metaphors in the area of neurochemistry, especially NMDA receptors. An important area of drug design is the inhibition of angiotensin II enzyme by the use of losartan. This commercial drug contains a tetrazole moiety that can be modified using the squaryl group to give a semisquarate derivative. These concepts can extend to the semisquarate of ibuprofen. Moreover, a discussion on peptidomimetics regarding the substitution of the peptide bond for squaramide allows for a change in the biological properties due to modification at the peptide bond. Furthermore, the topic on how squaryl metaphors can be exploited primarily by the central 1,3-hydroxyamide sequence to the generation of a novel class of HIV protease inhibitors. Also, squaryl metaphors can be used to develop potential inhibitors of glutathione and novel anti-migraine drugs. The discussion continues on the design of anticancer drugs: in particular, a novel class of metalloproteases, including phosphonates for semisquaramides, leading to squaryl nucleosides. This review concludes with the application of squaryl metaphors in the design of positron emission tomography (PET) and magnetic resonance imaging (MRI) agents towards theranostics. describe the ability of individual functional chemical groups to mimic other moieties [2,3]. KeywordsErlenmeyer rationalised these concepts and categorised isosteres into atoms, ions and molecules based on the valence level of electrons [4]. A further understanding by Friedman led to the term bioisosterism to include all atoms and molecules that fit the broadest definition of isosteres [5]. This approach was independent of whether the drug was an agonist or an antagonist towards biological activity.Moreover, Thornber applied the term bioisosterism to include subunits, groups or molecules that possess physicochemical properties of similar biological effects [6]. Finally, in 1991 Burger widened the definition of bioisosteres to include compounds or groups that possess similar molecular shapes and volumes independent of agonists or antagonists [7]. REVIEW ARTICLE Squaryl KitsonThese bioisosteres would require approximately the same distribution of electrons and give a high probability of generating comparable physical properties such as hydrophobicity [8]. Currently, bioisosterism is one of the most useful tools to the medicinal chemist in rational drug design and in particular regarding the carboxylic acid bioisosteres [9]. The carboxylic acid functional ...

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“…The ionization constant, as measured by pK a , is a useful thermodynamic parameter to modulate several key molecular properties (Charifson & Walters, 2014;Manallack et al 2013). Specifically, drug distribution and diffusion rely heavily on the ionized state of the drugs at a physiological pH because the neutral species of compounds are more lipophilic, whereas ionized ones are polar and water soluble.…”

Section: Ionization Constantmentioning

confidence: 99%

In silicoADME/T modelling for rational drug design

Wang

Xing

Yue

et al. 2015

Quart. Rev. Biophys.

270

155

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Abstract. In recent decades, in silico absorption, distribution, metabolism, excretion (ADME), and toxicity (T) modelling as a tool for rational drug design has received considerable attention from pharmaceutical scientists, and various ADME/T-related prediction models have been reported. The high-throughput and low-cost nature of these models permits a more streamlined drug development process in which the identification of hits or their structural optimization can be guided based on a parallel investigation of bioavailability and safety, along with activity. However, the effectiveness of these tools is highly dependent on their capacity to cope with needs at different stages, e.g. their use in candidate selection has been limited due to their lack of the required predictability. For some events or endpoints involving more complex mechanisms, the current in silico approaches still need further improvement. In this review, we will briefly introduce the development of in silico models for some physicochemical parameters, ADME properties and toxicity evaluation, with an emphasis on the modelling approaches thereof, their application in drug discovery, and the potential merits or deficiencies of these models. Finally, the outlook for future ADME/T modelling based on big data analysis and systems sciences will be discussed.

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The significance of acid/base properties in drug discovery

Cited by 268 publications

References 59 publications

Advances in microspeciation of drugs and biomolecules: Species-specific concentrations, acid-base properties and related parameters

Advances in microspeciation of drugs and biomolecules: Species-specific concentrations, acid-base properties and related parameters

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

In silicoADME/T modelling for rational drug design

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