Structure-based shape pharmacophore modeling for the discovery of novel anesthetic compounds

Ebalunode, Jerry O.; Dong, Xueyi; Ouyang, Zheng; Liang, Jie; Eckenhoff, Roderic G.; Zheng, Weifan

doi:10.1016/j.bmc.2009.05.060

Cited by 13 publications

(8 citation statements)

References 24 publications

(27 reference statements)

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“…While a strong correlation exists between apoferritin binding and anesthetic potency, 15 it was striking that a correlation between apoferritin binding and flunitrazepam binding to cortical membranes was absent. Select top active compounds, including the 6-phenylpyridazin-3(2H)-one chemotype representative, appear to not only not enhance, but to inhibit flunitrazepam binding.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, this site bears secondary, tertiary and quaternary structural similarity to the transmembrane region of ligand gated channels. 15 We further have described a screening assay based on competitive binding, employing apoferritin as a surrogate for the unknown anesthetic protein target and the fluorescent anesthetic 1-aminoanthracene (1-AMA) as a reporter molecule. 16 Having miniaturized the assay, it became possible to perform high-throughput screens on large numbers of small molecules, to better explore chemical-space.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of a Novel General Anesthetic Chemotype Using High-throughput Screening

McKinstry-Wu

Rai

et al. 2015

Anesthesiology

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Background The development of novel anesthetics has historically been a process of combined serendipity and empiricism, with most recent new anesthetics developed via modification of existing anesthetic structures. Methods Using a novel high-throughput screen employing the fluorescent anesthetic 1-aminoanthracene (1-AMA) and apoferritin as a surrogate for on-pathway anesthetic protein target(s), we screened a 350,000 compound library for competition with 1-AMA-apoferritin binding. Hit compounds meeting structural criteria had their binding affinities for apoferritin quantified with isothermal titration calorimetry and were tested for γ-aminobutyric acid type A-receptor binding using a flunitrazepam binding assay. Chemotypes with a strong presence in the top 700 and exhibiting activity via isothermal titration calorimetry were selected for medicinal chemistry optimization including testing for anesthetic potency and toxicity in an in vivo Xenopus laevis tadpole assay. Compounds with low toxicity and high potency were tested for anesthetic potency in mice. Results From an initial chemical library of over 350,000 compounds, we identified 2,600 compounds that potently inhibited 1-AMA binding to apoferritin. A subset of compounds chosen by structural criteria (700) was successfully reconfirmed using the initial assay. Based upon a strong presence in both the initial and secondary screens the 6-phenylpyridazin-3(2H)-one chemotype was assessed for anesthetic activity in tadpoles. Medicinal chemistry efforts identified four compounds with high potency and low toxicity in tadpoles, two were found to be effective novel anesthetics in mice. Conclusions We demonstrate the first use of a high-throughput screen to successfully identify a novel anesthetic chemotype and show mammalian anesthetic activity for members of that chemotype.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel General Anesthetic Chemotype Using High-throughput Screening

McKinstry-Wu

Rai

et al. 2015

Anesthesiology

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“…22,23 Most commonly, chemical similarity measures based on two or three-dimensional structure or molecular shape are employed in ligand based virtual screening efforts 24,25 as well as in optimization tools such as quantitative structureactivity relationship, 26,27 molecular docking 28 and pharmacophore mapping. 29,30 There have been numerous reports of the design and optimization of peptide-derived agents geared towards inhibition of the broad class of growth factor receptor bound adaptor proteins, via their SH2 domains. 31,32 A variety of tactics ranging from phosphorylation 33 macrocyclization 34 conformational restriction 35 and use of amino acid surrogates 36 have been exploited to optimize the binding affinity of the lead peptides.…”

Section: Introductionmentioning

confidence: 99%

Benzopyrazine derivatives: A novel class of growth factor receptor bound protein 7 antagonists

Ambaye

Gunzburg

Lim

et al. 2011

Bioorganic & Medicinal Chemistry

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“…A computational method in ligand-based drug design, pharmacophore modeling was developed to be an effective and rapid virtual screening which uses the architecture and physicochemical texture of the binding pocket to perform the virtual screening experiments [12]. One of the software which is widely used in Pharmacophore Modeling is catalyst, has been re-engineered for improvement of usability in Discovery Studio ® [13].…”

Section: Introductionmentioning

confidence: 99%

Pharmacophore Modeling of N1-alkyltheobromine as Histamine-H1 Receptor Antagonist

Hariono¹,

Wahab²

2015

IJMO

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Abstract-Previous studies worked on the evaluation a few alkylxanthine derivatives synthesized from theobromine, exhibiting micromolar activities of the compounds against histamine in vitro. The structure-activity relationships study showed that the elongation of alkyl group at N 1 of xanthine ring increased the tracheospasmolytic activity. This result opened the opportunity for alkylxanthine to be developed as antihistamine. Presently, we elucidate the mechanism of N 1 -alkylxanthine derivatives as antihistamine at a molecular level using pharmacophore modeling. The pharmacophore model was generated from a series of Histamine-H1 antagonists employing hydrogen bond acceptor (HBA), hydrogen bond donor (HBD) and two hydrophobic features and used as a search queries to map the N 1 -alkylxanthine derivatives as Histamine-H1 antagonist. The results showed that all the designed ligands can adopt the pharmacophore features model providing the insight understanding about the opportunities of the N 1 -alkylxanthine as Histamine-H1 antagonists.

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Structure-based shape pharmacophore modeling for the discovery of novel anesthetic compounds

Cited by 13 publications

References 24 publications

Discovery of a Novel General Anesthetic Chemotype Using High-throughput Screening

Discovery of a Novel General Anesthetic Chemotype Using High-throughput Screening

Benzopyrazine derivatives: A novel class of growth factor receptor bound protein 7 antagonists

Pharmacophore Modeling of N1-alkyltheobromine as Histamine-H1 Receptor Antagonist

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