Pharmacophore Modeling for Qualitative Prediction of Antiestrogenic Activity

Brogi, Simone; Kladi, Maria; Vagias, Constantinos; Papazafiri, Panagiota; Roussis, Vassilios; Tafi, Andrea

doi:10.1021/ci900254b

Cited by 33 publications

(27 citation statements)

References 33 publications

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“…The uncertainty value affects the categorization of ligands in the data set as either active or inactive compounds and is used during the constructive and subtractive phases. Here, an uncertainty value of 2.0 was more suitable for our data set because the compound activities spanned the requisite 4 orders of magnitude; this choice has been confirmed by evidence in the literature [35,36] . The feature mapping/DS protocol was used to identify common features present in the active inhibitors of BChE.…”

Section: Pharmacophore Modelingmentioning

confidence: 74%

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

Sakkiah

Lee

2012

Acta Pharmacol Sin

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Aim: To identify the critical chemical features, with reliable geometric constraints, that contributes to the inhibition of butyrylcholinesterase (BChE) function. Methods: Ligand-based pharmacophore modeling was used to identify the critical chemical features of BChE inhibitors. The generated pharmacophore model was validated using various techniques, such as Fischer's randomization method, test set, and decoy set. The best pharmacophore model was used as a query in virtual screening to identify novel scaffolds that inhibit BChE. Compounds selected by the best hypothesis in the virtual screening were tested for drug-like properties, and molecular docking study was applied to determine the optimal orientation of the hit compounds in the BChE active site. To find the reactivity of the hit compounds, frontier orbital analysis was carried out using density functional theory. Results: Based on its correlation coefficient (0.96), root mean square (RMS) deviation (1.01), and total cost (105.72), the quantitative hypothesis Hypo1 consisting of 2 HBA, 1 Hy-Ali, and 1 Hy-Ar was selected as the best hypothesis. Thus, Hypo1 was used as a 3D query in virtual screening of the Maybridge and Chembridge databases. The hit compounds were filtered using ADMET, Lipinski's Rule of Five, and molecular docking to reduce the number of false positive results. Finally, 33 compounds were selected based on their critical interactions with the significant amino acids in BChE's active site. To confirm the inhibitors' potencies, the orbital energies, such as HOMO and LUMO, of the hit compounds and 7 training set compounds were calculated. Among the 33 hit compounds, 10 compounds with the highest HOMO values were selected, and this set was further culled to 5 compounds based on their energy gaps important for stability and energy transfer. From the overall results, 5 hit compounds were confirmed to be potential BChE inhibitors that satisfied all the pharmacophoric features in Hypo1. Conclusion: This study pinpoints important chemical features with geometric constraints that contribute to the inhibition of BChE activity. Five compounds are selected as the best hit BchE-inhibitory compounds.

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Section: Pharmacophore Modelingmentioning

confidence: 74%

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

Sakkiah

Lee

2012

Acta Pharmacol Sin

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“…The need for the development of a computational (in silico) prescreening method for activity prediction led Brogi and co-workers to the creation of a ligand-based pharmacophore for MCF-7 cells, which was able to predict with accuracy the cytotoxicity levels for an array of compounds against this cell line [874].…”

Section: Cytotoxic Activitymentioning

confidence: 99%

The Laurencia Paradox: An Endless Source of Chemodiversity

Harizani

Iοannou

Roussis

2016

Progress in the Chemistry of Organic Natural Products

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Nature, the most prolific source of biological and chemical diversity, has provided mankind with treatments for health problems since ancient times and continues to be the most promising reservoir of bioactive chemicals for the development of modern drugs. In addition to the terrestrial organisms that still remain a promising source of new bioactive metabolites, the marine environment, covering approximately 70% of the Earth's surface and containing a largely unexplored biodiversity, offers an enormous resource for the discovery of novel compounds. According to the MarinLit database, more than 27,000 metabolites from marine macro- and microorganisms have been isolated to date providing material and key structures for the development of new products in the pharmaceutical, food, cosmeceutical, chemical, and agrochemical sectors. Algae, which thrive in the euphotic zone, were among the first marine organisms that were investigated as sources of food, nutritional supplements, soil fertilizers, and bioactive metabolites.Red algae of the genus Laurencia are accepted unanimously as one of the richest sources of new secondary metabolites. Their cosmopolitan distribution, along with the chemical variation influenced to a significant degree by environmental and genetic factors, have resulted in an endless parade of metabolites, often featuring multiple halogenation sites.The present contribution, covering the literature until August 2015, offers a comprehensive view of the chemical wealth and the taxonomic problems currently impeding chemical and biological investigations of the genus Laurencia. Since mollusks feeding on Laurencia are, in many cases, bioaccumulating, and utilize algal metabolites as chemical weaponry against natural enemies, metabolites of postulated dietary origin of sea hares that feed on Laurencia species are also included in the present review. Altogether, 1047 secondary metabolites, often featuring new carbocyclic skeletons, have been included.The chapter addresses: (1) the "Laurencia complex", the botanical description and the growth and population dynamics of the genus, as well as its chemical diversity and ecological relations; (2) the secondary metabolites, which are organized according to their chemical structures and are classified into sesquiterpenes, diterpenes, triterpenes, acetogenins, indoles, aromatic compounds, steroids, and miscellaneous compounds, as well as their sources of isolation which are depicted in tabulated form, and (3) the biological activity organized according to the biological target and the ecological functions of Laurencia metabolites.

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“…COR627 was identified by means of a virtual screening protocol, according to a procedure recently adopted by some of us for other targets (see Brogi et al, 2009Brogi et al, , 2011.…”

Section: Resultsmentioning

confidence: 99%

Characterization of COR627 and COR628, Two Novel Positive Allosteric Modulators of the GABA_B Receptor

Castelli¹,

Casu²,

Casti³

et al. 2011

J Pharmacol Exp Ther

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The potential efficacy of GABA B receptor agonists in the treatment of pain, drug addiction, epilepsy, cognitive dysfunctions, and anxiety disorders is supported by extensive preclinical and clinical evidence. However, the numerous side effects produced by the GABA B receptor agonist baclofen considerably limit the therapeutic use of this compound. The identification of positive allosteric modulators (PAMs) of the GABA B receptor may constitute a novel approach in the pharmacological manipulation of the GABA B receptor, leading to fewer side effects. The present study reports the identification of two novel compounds, methyl 2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR627) and methyl 2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR628), which act as GABA B PAMs in 1) rat cortical membranes and 2) in vivo assay. Both compounds potentiated GABA-and baclofen-stimulated guanosine 5Ј-O-(3-[ 35 S]thio)-triphosphate binding to native GABA B receptors, while producing no effect when given alone. GABA concentration-response curves in the presence of fixed concentrations of COR627 and COR628 revealed an increase of potency of GABA rather than its maximal efficacy. In radioligand binding experiments [displacement of the GABA B receptor antago-, both COR627 and COR628 increased the affinity of high-and low-affinity binding sites for GABA, producing no effect when administered alone up to a concentration of 1 mM. In vivo experiments indicated that pretreatment with per se ineffective doses of COR627 and COR628 potentiated the sedative/hypnotic effect of baclofen. In conclusion, COR627 and COR628 may represent two additional tools for use in investigating the roles and functions of positive allosteric modulatory binding sites of the GABA B receptor.

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Pharmacophore Modeling for Qualitative Prediction of Antiestrogenic Activity

Cited by 33 publications

References 33 publications

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

The Laurencia Paradox: An Endless Source of Chemodiversity

Characterization of COR627 and COR628, Two Novel Positive Allosteric Modulators of the GABA_B Receptor

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Pharmacophore Modeling for Qualitative Prediction of Antiestrogenic Activity

Cited by 33 publications

References 33 publications

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

The Laurencia Paradox: An Endless Source of Chemodiversity

Characterization of COR627 and COR628, Two Novel Positive Allosteric Modulators of the GABAB Receptor

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Characterization of COR627 and COR628, Two Novel Positive Allosteric Modulators of the GABA_B Receptor