B
            <scp>ioster</scp>
            : A Database of Bioisosteres and Bioanalogues

Ujváry, István; J, Hayward

doi:10.1002/9783527654307.ch4

Cited by 8 publications

(6 citation statements)

References 57 publications

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“…For generating the bioisosteric replacements of the amidine and guanidine recognition motifs we applied literature sources [33] and software [34] (30 selected bioisosteric transformations can be found: Supplementary Materials, Scheme S1). Relatively few compounds (1100) were found in the vendor databases that contained the generated bioisosteric replacements and those compounds were also used for similarity search matching their structures with the reference compounds.…”

Section: Resultsmentioning

confidence: 99%

Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches

Szilágyi¹,

Hajdú

Flachner³

et al. 2019

Molecules

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The complement system is associated with various diseases such as inflammation or auto-immune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since it blocks the system at an early stage of the complement cascade. Designing C1 inhibitors is particularly challenging since known inhibitors are restricted to a narrow bioactive chemical space in addition selectivity over other serine proteases is an important requirement. The typical architecture of a small molecule inhibitor of C1s contains an amidine (or guanidine) residue, however, the discovery of non-amidine inhibitors might have high value, particularly if novel chemotypes and/or compounds displaying improved selectivity are identified. We applied various virtual screening approaches to identify C1s focused libraries that lack the amidine/guanidine functionalities, then the in silico generated libraries were evaluated by in vitro biological assays. While 3D structure-based methods were not suitable for virtual screening of C1s inhibitors, and a 2D similarity search did not lead to novel chemotypes, pharmacophore model generation allowed us to identify two novel chemotypes with submicromolar activities. In three screening rounds we tested altogether 89 compounds and identified 20 hit compounds (<10 μM activities; overall hit rate: 22.5%). The highest activity determined was 12 nM (1,2,4-triazole), while for the newly identified chemotypes (1,3-benzoxazin-4-one and thieno[2,3-d][1,3]oxazin-4-one) it was 241 nM and 549 nM, respectively.

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Section: Resultsmentioning

confidence: 99%

Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches

Szilágyi¹,

Hajdú

Flachner³

et al. 2019

Molecules

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“…44 We now have tested by molecular modeling the hypothesis that C-7-oxidized metabolites of CBD are involved in its observed phenytoin-like effects. This hypothesis has been inspired by the reported bioisosterism [54][55][56] of the hydantoin ring, present in PHT, and the carboxylic acid functionality, present in dominant human metabolites of CBD. Herein we report the results of molecular modeling studies comparing the electrostatic and conformational features of CBD and main phytocannabinoid metabolites with those of PHT.…”

Section: Resultsmentioning

confidence: 99%

Towards Understanding the Phenytoin-like Antiepileptic Effect of Cannabidiol and Related Phytocannabinoid Metabolites Insights from Molecular Modeling

Ujváry¹,

Lopata²

2018

Preprint

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<div> Cannabidiol (CBD), a nonpsychotropic constituent of <i>Cannabis sativa</i>, has recently been approved by the US FDA for the treatment of certain forms of pediatric epilepsy. The mechanism by which CBD exerts its antiepileptic effects, however, is not known. Herein we describe the results of molecular modeling studies comparing the stereoelectronic properties of phenytoin (PHT) with those of CBD and its carboxylic acid metabolite, as well as of 7-hydroxycannabidivarin. Also, the cyclohexenecarboxylic acid core of 7-COOH-CBD perfectly mimics the unsaturated bioactive metabolite of the commonly used antiepileptic valproic acid was also noted. We propose that C–7 oxidized phytocannabinoid metabolites are involved in the phenytoin-like anticonvulsant effects of the parent phytocannabinoid drugs.</div>

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“…Since it has been established that urea-based compounds and their classical bioisosteres might suffer from developmentability issues in preclinical and clinical settings, 61 several groups experimented with novel bioisosteres for urea to obtain CXCR2 antagonists with improved pharmacological and pharmacokinetic properties. One scaffold disclosed and explored by GSK was 2-aminopyrimidin-4(1 H )-one, a cyclised form of the urea motif.…”

Section: Discovery and Development Of Allosteric Intracellular Chemok...mentioning

confidence: 99%

Targeting chemokine receptors from the inside-out: discovery and development of small-molecule intracellular antagonists

2022

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B ioster : A Database of Bioisosteres and Bioanalogues

Cited by 8 publications

References 57 publications

Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches

Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches

Towards Understanding the Phenytoin-like Antiepileptic Effect of Cannabidiol and Related Phytocannabinoid Metabolites Insights from Molecular Modeling

Targeting chemokine receptors from the inside-out: discovery and development of small-molecule intracellular antagonists

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