Exploring the Influence of the Protein Environment on Metal-Binding Pharmacophores

Martin, David P.; Blachly, Patrick G.; McCammon, J. Andrew; Cohen, Seth M.

doi:10.1021/jm500984b

Cited by 29 publications

(40 citation statements)

References 78 publications

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“…The lack of change observed in dihedral angle and coordination geometry with thiotropolone and 1,2-HOPTO ( O,S donor MBPs) when binding to hCAII and hCAII L198G is consistent with previous studies, where changes in coordination geometry and binding mode for 1,2-HOPTO were only observed when unfavorable interactions were introduced by derivatization of the 1,2-HOPTO MBP [38]. On the other hand, MBPs that bind only with O,O donor atoms, such as tropolone, are found to be quite sensitive to perturbations from the ideal coordination geometry, as highlighted by changes in the dihedral angle upon binding.…”

Section: Discussionsupporting

confidence: 91%

Effect of donor atom identity on metal-binding pharmacophore coordination

et al. 2017

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The inhibition and binding of three metal-binding pharmacophores (MBPs), 2-hydroxycyclohepta-2,4,6-trien-1-one (tropolone), 2-mercaptopyridine-N-oxide (1,2-HOPTO), and 2-hydroxycyclohepta-2,4,6-triene-1-thione (thiotropolone) to human carbonic anhydrase II (hCAII) and a mutant protein hCAII L198G were investigated. These MBPs displayed bidentate coordination to the active site Zn(II) metal ion, but the MBPs respond to the mutation of L198G differently, as characterized by inhibition activity assays and X-ray crystallography. The L198G mutation increases the active site volume thereby decreasing the steric pressure exerted on MBPs upon binding, allowing changes in MBP coordination to be observed. When comparing the binding mode of tropolone to thiotropolone or 1,2-HOPTO (O,O versus O,S donor sets), structural modifications of the hCAII active site were shown to have a stronger effect on MBPs with an O,O versus O,S donor set. These findings were corroborated with density functional theory (DFT) calculations of model coordination complexes. These results suggest that the MBP binding geometry is a malleable interaction, particularly for certain ligands, and that the identity of the donor atoms still play a significant role in ligand coordination. Understanding underlying interactions between a MBP and a metalloenzyme active site may aid in the design and development of potent metalloenzyme inhibitors.

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Section: Discussionsupporting

confidence: 91%

Effect of donor atom identity on metal-binding pharmacophore coordination

et al. 2017

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“…A likely reason for the selectivity observed in hCAII, as previously detailed in work by Martin, [41] is that the protein active site environment can impart a great deal of control on what ligands are able to effectively access the Zn 2+ ion within the active site. The hCAII active site is fairly sterically and electrostatically constricted with both hydrophobic and hydrophilic regions, and therefore only allows a select number of ligands to bind efficiently.…”

Section: Resultsmentioning

confidence: 99%

Isosteres of hydroxypyridinethione as drug-like pharmacophores for metalloenzyme inhibition

et al. 2018

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Hydroxypyridinethiones (HOPTOs) are strong ligands for metal ions and potentially useful pharmacophores for inhibiting metalloenzymes relevant to human disease. However, HOPTOs have been sparingly used in drug discovery efforts due, in part, to concerns that this scaffold will act as a promiscuous, non-selective metalloenzyme inhibitor, as well as possess poor pharmacokinetics (PK), which may undermine drug candidates containing this functional group. To advance HOPTOs as a useful pharmacophore for metalloenzyme inhibitors, a library of 22 HOPTO isostere compounds has been synthesized and investigated. This library demonstrates that it is possible to maintain the core metal-binding pharmacophore (MBP) while generating diversity in structure, electronics, and PK properties. This HOPTO library has been screened against a set of four different metalloenzymes, demonstrating that while the same metal-binding donor atoms are maintained, there is a wide range of activity between metalloenzyme targets. Overall, this work shows that HOPTO isosteres are useful MBPs and valuable scaffolds for metalloenzyme inhibitors.

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“…[8] Cohen et al showedt hat methyl groups in various positions on pyrithione exert as ignificant effect on the affinity in am etalloenzyme active site of human carbonic anhydrase II (hCAII). [21] The same group proceeded to prepare 21 more pyrithione analogues and furthers tudied the structure-activity relationship of metalbinding pharmacophores. [22] With thesed ata in hand, we decided to preparea na rray of ten organoruthenium(II) chlorido (1a-e)a nd pta (2a-e)c omplexes ( Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Towards Identification of Essential Structural Elements of Organoruthenium(II)‐Pyrithionato Complexes for Anticancer Activity

Kladnik

Kljun

Burmeister

et al. 2019

Chemistry A European J

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An organoruthenium(II) complex with pyrithione (2-mercaptopyridine N-oxide) 1a has previously been identified by our group as ac ompound with promising anticancer potential without cytotoxicity towards non-cancerous cells. To expand the rather limited research on compounds of this type, an array of novel chlorido and 1,3,5-triaza-7-phosphaadamantane( pta) organoruthenium(II) complexesw ith methyl-substituted pyrithiones has been prepared. After thorough investigation of the aqueous stability of these complexes, their modeso fa ction have been elucidated at the cellular level.M inor structurala lterations in the rutheni-um-pyrithionato compounds resulted in fine-tuning of their cytotoxicities. The best performing compounds, 1b and 2b, with ac hlorido or pta ligand bound to ruthenium, respectively,and amethyl group at the 3-position of the pyrithione scaffold, have been further investigated. Both compounds trigger early apoptosis, induce the generation of reactive oxygen speciesa nd G1 arrest in A549 cancerc ells, and show no strong interaction with DNA. However,o nly 1b also inhibits thioredoxin reductase.W ound healing assays and mitochondrial function evaluation have revealed differences between these two compounds at the cellular level. Figure 2. Structures of the prepared ligands and reaction path leadingt o the organoruthenium(II) chlorido (1a-e)a nd pta (2a-e)complexes.

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Exploring the Influence of the Protein Environment on Metal-Binding Pharmacophores

Cited by 29 publications

References 78 publications

Effect of donor atom identity on metal-binding pharmacophore coordination

Effect of donor atom identity on metal-binding pharmacophore coordination

Isosteres of hydroxypyridinethione as drug-like pharmacophores for metalloenzyme inhibition

Towards Identification of Essential Structural Elements of Organoruthenium(II)‐Pyrithionato Complexes for Anticancer Activity

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