Molecular Shape and Medicinal Chemistry: A Perspective

Nicholls, Anthony; McGaughey, Georgia B.; Sheridan, Robert P.; Good, Andrew C.; Warren, Gregory L.; Mathieu, Magali; Muchmore, Steven W.; Brown, Scott P.; Grant, Jennifer; Haigh, James A.; Nevins, Neysa; Jain, Ajay N.; Kelley, Brian P.

doi:10.1021/jm900818s

Cited by 285 publications

(262 citation statements)

References 92 publications

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“…46 Large ligands tend to have many rotatable bonds, and hence require exhaustive sampling of their conformational space. The default settings in OMEGA were found to be suitable for the the small ace ligands, but only give a modest improvement for about 25% of the DUD targets.…”

Section: Discussion Overall Analysismentioning

confidence: 99%

Comprehensive Comparison of Ligand-Based Virtual Screening Tools Against the DUD Data set Reveals Limitations of Current 3D Methods

Venkatraman

Pérez‐Nueno

Mavridis

et al. 2010

J. Chem. Inf. Model.

126

156

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In recent years, many virtual screening (VS) tools have been developed that employ different molecular representations and have different speed and accuracy characteristics. In this paper, we compare ten popular ligand-based VS tools using the publicly available Directory of Useful Decoys (DUD) dataset comprising over 100,000 compounds distributed across 40 protein targets. The DUD was developed initially to evaluate docking algorithms, but our results from an operational correlation analysis show that it is also well suited for comparing ligand-based VS tools. Although it is conventional wisdom that 3D molecular shape is an important determinant of biological activity, our results based on permutational significance tests of several commonly used VS metrics show that the 2D fingerprint-based methods generally give better VS performance than the 3D shape-based approaches for surprisingly many of the DUD targets. In order to help understand this finding, we have analysed the nature of the scoring functions used and the composition of the DUD dataset itself. We propose that in order to * To whom correspondence should be addressed † INRIA Nancy Grand Est, LORIA, 54506, Vandoeuvre-lès-Nancy, France ‡ Contributed equally to this work 1 improve the VS performance of current 3D methods, it will be necessary to devise screening queries which can represent multiple possible conformations and which can exploit knowledge of known actives that span multiple scaffold families.

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Section: Discussion Overall Analysismentioning

confidence: 99%

Comprehensive Comparison of Ligand-Based Virtual Screening Tools Against the DUD Data set Reveals Limitations of Current 3D Methods

Venkatraman

Pérez‐Nueno

Mavridis

et al. 2010

J. Chem. Inf. Model.

126

156

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“…45 However, molecular shape or chemoinformatic similarity algorithms for drug discovery have not been widely used in metabolic engineering for identification of regulatory ligand and cognate transcription factor pair. The similarity assessment for small molecules is often too stringent for molecules of interest in metabolic engineering.…”

mentioning

confidence: 99%

Development of a Transcription Factor-Based Lactam Biosensor

et al. 2017

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Lactams are an important class of commodity chemicals used in the manufacture of nylons, with millions of tons produced every year. Biological production of lactams could be greatly improved by high-throughput sensors for lactam biosynthesis. To identify biosensors of lactams, we applied a chemoinformatic approach inspired by small molecule drug discovery. We define this approach as analogue generation toward catabolizable chemicals or AGTC. We discovered a lactam biosensor based on the ChnR/Pb transcription factor-promoter pair. The microbial biosensor is capable of sensing ε-caprolactam, δ-valerolactam, and butyrolactam in a dose-dependent manner. The biosensor has sufficient specificity to discriminate against lactam biosynthetic intermediates and therefore could potentially be applied for high-throughput metabolic engineering for industrially important high titer lactam biosynthesis.

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“…These 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].…”

Section: Kitsonmentioning

confidence: 99%

“…These bioisosteres would require approximately the same distribution of electrons and give a high probability of generating comparable physical properties such as hydrophobicity [8].…”

Section: Kitsonmentioning

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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Molecular Shape and Medicinal Chemistry: A Perspective

Cited by 285 publications

References 92 publications

Comprehensive Comparison of Ligand-Based Virtual Screening Tools Against the DUD Data set Reveals Limitations of Current 3D Methods

Comprehensive Comparison of Ligand-Based Virtual Screening Tools Against the DUD Data set Reveals Limitations of Current 3D Methods

Development of a Transcription Factor-Based Lactam Biosensor

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

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