Potholing of the hydrophobic heme oxygenase-1 western region for the search of potent and selective imidazole-based inhibitors

Salerno, Loredana; Amata, Emanuele; Romeo, Giuseppe; Marrazzo, Agostino; Prezzavento, Orazio; Floresta, Giuseppe; Sorrenti, Valeria; Barbagallo, Ignazio; Rescifina, Antonio

doi:10.1016/j.ejmech.2018.02.007

Cited by 41 publications

(47 citation statements)

References 52 publications

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“…Our research interest is related to the development of new antitumor compounds and more specifically selective HO-1 and mixed HO-1/HO-2 inhibitors [ 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. To this extent, we constructed a ligand database with more than 400 molecules (HemeOxDB, ), similar to the one we built for sigma-2 receptor ligands [ 25 , 26 ], that incorporates the entire amount of published HO-1 and HO-2 inhibitors [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Structural Insight into Inhibitors of Heme Oxygenase-1 (HO-1) by New Imidazole-Based Compounds: Biochemical and In Vitro Anticancer Activity Evaluation

et al. 2018

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In this paper, the design, synthesis, and molecular modeling of a new azole-based HO-1 inhibitors was reported, using compound 1 as a lead compound, in which an imidazole moiety is linked to a hydrophobic group by means of an ethanolic spacer. The tested compounds showed a good inhibitor activity and possessed IC50 values in the micromolar range. These results were obtained by targeting the hydrophobic western region. Molecular modeling studies confirmed a consolidated binding mode in which the nitrogen of the imidazolyl moiety coordinated the heme ferrous iron, meanwhile the hydrophobic groups were located in the western region of HO-1 binding pocket. Moreover, the new compounds were screened for in silico ADME-Tox properties to predict drug-like behavior with convincing results. Finally, the in vitro antitumor activity profile of compound 1 was investigated in different cancer cell lines and nanomicellar formulation was synthesized with the aim of improving compound’s 1 water solubility. Finally, compound 1 was tested in melanoma cells in combination with doxorubicin showing interesting synergic activity.

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Section: Introductionmentioning

confidence: 99%

Novel Structural Insight into Inhibitors of Heme Oxygenase-1 (HO-1) by New Imidazole-Based Compounds: Biochemical and In Vitro Anticancer Activity Evaluation

et al. 2018

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“…In line with our recent interest in the development of QSAR models and related applications [20][21][22][23][24][25][26][27], we recently produced the first 3D-QSAR model for the description of a dataset of selective and potent FABP4 inhibitors [28,29]. The 3D-QSAR model was then combined with a scaffold-hopping analysis, allowing the design of new potent molecules able to interact with the binding site and inhibit the FABP4; finally, three of the ligands suggested by the scaffold-hopping analysis were synthesized and tested in vitro yielding IC50 values between 3.70 and 5.59 M.…”

Section: Introductionmentioning

confidence: 55%

Computational Tools in the Discovery of FABP4 Ligands: A Statistical and Molecular Modeling Approach

Floresta

Gentile

Perrini

et al. 2019

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Small molecule inhibitors of adipocyte fatty-acid binding protein 4 (FABP4) have got interest following the recent publication of their pharmacologically beneficial effects. Recently it comes out that FABP4 is an attractive molecular target for the treatment of type 2 diabetes, other metabolic diseases, and some type of cancers. In the past years, hundreds of effective FABP4 inhibitors have been synthesized and discovered but, unfortunately, none of them is in the clinical research phase. The field of computer-aided drug design seems to be promising and useful for the identification of FABP4 inhibitors; hence, different structure- and ligand-based computational approaches were already performed for their identification. In this paper, we searched for new potentially active FABP4 ligands in the Marine Natural Products (MNP) database. 14,492 compounds were retrieved from this database and filtered through a statistical and computational filter. Seven compounds were suggested by our methodology to possess a potential inhibitory activity upon FABP4 in the range of 79–245 nM. ADMET properties prediction were performed to validate the hypothesis of the interaction with the intended target and to assess the drug-likeness of these derivatives; from these analyses, three molecules resulted as excellent candidates for becoming new drugs.

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“…The software CORAL (CORrelation And Logic, version 2016, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy) was used for building the 2D-QSAR model using 548 σ 2 receptor selective ligands over the σ 1 receptor, as previously reported [ 33 , 34 ]. The unique SMILES composing the blue dataset were converted in order to have a SMILES depiction that was equal to that used for generating the model (vide supra).…”

Section: Methodsmentioning

confidence: 99%

“…Since structure and ligand-based computer-aided drug design are nowadays effective and useful tools in rational drug design [ 34 , 35 , 36 , 37 , 38 , 39 ], we used them to allow the identification of new virtually potent and selective molecules that are able to interact with the σ 2 receptor. Therefore, herein, we report an investigation of new potentially σ 2 /TMEM97 receptor ligands among a database of 1517 “small” marine natural products, here named the Blue DataBase (BDB, Table S1 ), which was composed by the merging of the Seaweed Metabolite ( ) [ 40 ], the Chemical Entities of Biological Interest (ChEBI, ) [ 41 ] databases, and from the reference [ 42 ].…”

Section: Introductionmentioning

confidence: 99%

A Structure- and Ligand-Based Virtual Screening of a Database of “Small” Marine Natural Products for the Identification of “Blue” Sigma-2 Receptor Ligands

et al. 2018

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Sigma receptors are a fascinating receptor protein class whose ligands are actually under clinical evaluation for the modulation of opioid analgesia and their use as positron emission tomography radiotracers. In particular, peculiar biological and therapeutic functions are associated with the sigma-2 (σ2) receptor. The σ2 receptor ligands determine tumor cell death through apoptotic and non-apoptotic pathways, and the overexpression of σ2 receptors in several tumor cell lines has been well documented, with significantly higher levels in proliferating tumor cells compared to quiescent ones. This acknowledged feature has found practical application in the development of cancer cell tracers and for ligand-targeting therapy. In this context, the development of new ligands that target the σ2 receptors is beneficial for those diseases in which this protein is involved. In this paper, we conducted a search of new potential σ2 receptor ligands among a database of 1517 “small” marine natural products constructed by the union of the Seaweed Metabolite and the Chemical Entities of Biological Interest (ChEBI) Databases. The structures were passed through two filters that were constituted by our developed two-dimensional (2D) and three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) statistical models, and successively docked upon a σ2 receptor homology model that we built according to the FASTA sequence of the σ2/TMEM97 (SGMR2_HUMAN) receptor.

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Potholing of the hydrophobic heme oxygenase-1 western region for the search of potent and selective imidazole-based inhibitors

Cited by 41 publications

References 52 publications

Novel Structural Insight into Inhibitors of Heme Oxygenase-1 (HO-1) by New Imidazole-Based Compounds: Biochemical and In Vitro Anticancer Activity Evaluation

Novel Structural Insight into Inhibitors of Heme Oxygenase-1 (HO-1) by New Imidazole-Based Compounds: Biochemical and In Vitro Anticancer Activity Evaluation

Computational Tools in the Discovery of FABP4 Ligands: A Statistical and Molecular Modeling Approach

A Structure- and Ligand-Based Virtual Screening of a Database of “Small” Marine Natural Products for the Identification of “Blue” Sigma-2 Receptor Ligands

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