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Artikel: Identification and Development of BRD9 Chemical Probes.

Colarusso, Ester / Chini, Maria Giovanna / Bifulco, Giuseppe / Lauro, Gianluigi / Giordano, Assunta

2024 Band 17, Heft 3

Abstract: The development of BRD9 inhibitors involves the design and synthesis of molecules that can specifically bind the BRD9 protein, interfering with the function of the chromatin-remodeling complex ncBAF, with the main advantage of modulating gene expression ... ...

Abstract	The development of BRD9 inhibitors involves the design and synthesis of molecules that can specifically bind the BRD9 protein, interfering with the function of the chromatin-remodeling complex ncBAF, with the main advantage of modulating gene expression and controlling cellular processes. Here, we summarize the work conducted over the past 10 years to find new BRD9 binders, with an emphasis on their structure-activity relationships, efficacies, and selectivities in preliminary studies. BRD9 is expressed in a variety of cancer forms, hence, its inhibition holds particular significance in cancer research. However, it is crucial to note that the expanding research in the field, particularly in the development of new degraders, may uncover new therapeutic potentials.
Sprache	Englisch
Erscheinungsdatum	2024-03-19
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article ; Review
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph17030392
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: PharmaCore: The Automatic Generation of 3D Structure-Based Pharmacophore Models from Protein/Ligand Complexes.

De Vita, Simona / Colarusso, Ester / Chini, Maria Giovanna / Bifulco, Giuseppe / Lauro, Gianluigi

Journal of chemical information and modeling

2024

Abstract: In this work, we present PharmaCore: a new, completely automatic workflow aimed at generating three-dimensional (3D) structure-based pharmacophore models toward any target of interest. The proposed approach relies on using cocrystallized ligands to ... ...

Abstract	In this work, we present PharmaCore: a new, completely automatic workflow aimed at generating three-dimensional (3D) structure-based pharmacophore models toward any target of interest. The proposed approach relies on using cocrystallized ligands to create the input files for generating the pharmacophore hypotheses, integrating not only the three-dimensional structural information on the ligand but also data concerning the binding mode of these molecules put in the protein cavity. We developed a Python library that, starting from the specific UniProt ID of the protein under investigation as the only element that requires user intervention, subsequently collects and aligns the corresponding structures bearing a known ligand in a fully automated fashion, bringing them all into the same coordinate system. The protocol includes a final phase in which the aligned small molecules are used to produce the pharmacophore hypotheses directly onto the protein structure using a specific software, e.g., Phase (Schrödinger LLC). To validate the entire procedure and highlight the possible applications in the field of drug discovery and repositioning, we first generated pharmacophores for soluble epoxide hydrolase (sEH) and compared with already-published ones. Then, we reproduced the binding profile of a reported selective binder of ATAD2 bromodomain (AM879), testing it against a panel of 1741 pharmacophores related to 16 epigenetic proteins and automatically generated with PharmaCore, finally disclosing putative unprecedented off-targets. The computational predictions were successfully validated with AlphaScreen assays, highlighting the applicability of the proposed workflow in drug discovery and repositioning. Finally, the process was also validated on tankyrase 2 and SARS-CoV-2 M
Sprache	Englisch
Erscheinungsdatum	2024-05-10
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.3c01920
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Target identification by structure-based computational approaches: Recent advances and perspectives.

De Vita, Simona / Chini, Maria Giovanna / Bifulco, Giuseppe / Lauro, Gianluigi

Bioorganic & medicinal chemistry letters

2023 Band 83, Seite(n) 129171

Abstract: The use of computational techniques in the early stages of drug discovery has recently experienced a boost, especially in the target identification step. Finding the biological partner(s) for new or existing synthetic and/or natural compounds by "wet" ... ...

Abstract	The use of computational techniques in the early stages of drug discovery has recently experienced a boost, especially in the target identification step. Finding the biological partner(s) for new or existing synthetic and/or natural compounds by "wet" approaches may be challenging; therefore, preliminary in silico screening is even more recommended. After a brief overview of some of the most known target identification techniques, recent advances in structure-based computational approaches for target identification are reported in this digest, focusing on Inverse Virtual Screening and its recent applications. Moreover, future perspectives concerning the use of such methodologies, coupled or not with other approaches, are analyzed.
Mesh-Begriff(e)	Drug Discovery/methods ; Computational Biology
Sprache	Englisch
Erscheinungsdatum	2023-02-03
Erscheinungsland	England
Dokumenttyp	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2023.129171
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Insights into the Ligand Binding to Bromodomain-Containing Protein 9 (BRD9): A Guide to the Selection of Potential Binders by Computational Methods.

De Vita, Simona / Chini, Maria Giovanna / Bifulco, Giuseppe / Lauro, Gianluigi

Molecules (Basel, Switzerland)

2021 Band 26, Heft 23

Abstract: The estimation of the binding of a set of molecules against BRD9 protein was carried out through an in silico molecular dynamics-driven exhaustive analysis to guide the identification of potential novel ligands. Starting from eight crystal structures of ... ...

Abstract	The estimation of the binding of a set of molecules against BRD9 protein was carried out through an in silico molecular dynamics-driven exhaustive analysis to guide the identification of potential novel ligands. Starting from eight crystal structures of this protein co-complexed with known binders and one
Mesh-Begriff(e)	Amino Acids/chemistry ; Crystallization ; Data Analysis ; Ligands ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Binding ; Thermodynamics ; Transcription Factors/chemistry
Chemische Substanzen	Amino Acids ; Ligands ; Transcription Factors
Sprache	Englisch
Erscheinungsdatum	2021-11-27
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules26237192
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: NMR Metabolomics and Chemometrics of Commercial Varieties of

Samukha, Vadym / Fantasma, Francesca / D'Urso, Gilda / Caprari, Claudio / De Felice, Vincenzo / Saviano, Gabriella / Lauro, Gianluigi / Casapullo, Agostino / Chini, Maria Giovanna / Bifulco, Giuseppe / Iorizzi, Maria

Plants (Basel, Switzerland)

2024 Band 13, Heft 2

Abstract: The metabolite fingerprinting of four Italian commercial bean seed cultivars, i.e., ...

Abstract	The metabolite fingerprinting of four Italian commercial bean seed cultivars, i.e.,
Sprache	Englisch
Erscheinungsdatum	2024-01-13
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	2704341-1
ISSN	2223-7747
ISSN	2223-7747
DOI	10.3390/plants13020227
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Chemoproteomics Reveals USP5 (Ubiquitin Carboxyl-Terminal Hydrolase 5) as Promising Target of the Marine Polyketide Gracilioether A.

Capuano, Alessandra / D'Urso, Gilda / Aliberti, Michela / Ruggiero, Dafne / Terracciano, Stefania / Festa, Carmen / Tosco, Alessandra / Chini, Maria Giovanna / Lauro, Gianluigi / Bifulco, Giuseppe / Casapullo, Agostino

Marine drugs

2024 Band 22, Heft 1

Abstract: Mass spectrometry-based chemical proteomic approaches using limited proteolysis have become a powerful tool for the identification and analysis of the interactions between a small molecule (SM) and its protein target(s). Gracilioether A (GeA) is a ... ...

Abstract	Mass spectrometry-based chemical proteomic approaches using limited proteolysis have become a powerful tool for the identification and analysis of the interactions between a small molecule (SM) and its protein target(s). Gracilioether A (GeA) is a polyketide isolated from a marine sponge, for which we aimed to trace the interactome using this strategy. DARTS (Drug Affinity Responsive Target Stability) and t-LiP-MS (targeted-Limited Proteolysis-Mass Spectrometry) represented the main techniques used in this study. DARTS was applied on HeLa cell lysate for the identification of the GeA target proteins, and t-LiP-MS was employed to investigate the protein's regions involved in the binding with GeA. The results were complemented through the use of binding studies using Surface Plasmon Resonance (SPR) and in silico molecular docking experiments. Ubiquitin carboxyl-terminal hydrolase 5 (USP5) was identified as a promising target of GeA, and the interaction profile of the USP5-GeA complex was explained. USP5 is an enzyme involved in the pathway of protein metabolism through the disassembly of the polyubiquitin chains on degraded proteins into ubiquitin monomers. This activity is connected to different cellular functions concerning the maintenance of chromatin structure and receptors and the degradation of abnormal proteins and cancerogenic progression. On this basis, this structural information opens the way to following studies focused on the definition of the biological potential of Gracilioether A and the rational development of novel USP5 inhibitors based on a new structural skeleton.
Mesh-Begriff(e)	Humans ; HeLa Cells ; Molecular Docking Simulation ; Proteomics ; Polyketides ; Hydrolases ; Ubiquitins ; Heterocyclic Compounds, 3-Ring
Chemische Substanzen	gracilioether A ; Polyketides ; Hydrolases (EC 3.-) ; Ubiquitins ; Heterocyclic Compounds, 3-Ring
Sprache	Englisch
Erscheinungsdatum	2024-01-11
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	2175190-0
ISSN	1660-3397 ; 1660-3397
ISSN (online)	1660-3397
ISSN	1660-3397
DOI	10.3390/md22010041
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Prodrug Approach to Exploit (S) Alanine as Arginine Mimic Moiety in the Development of Protein Arginine Methyltransferase 4 Inhibitors.

Milite, Ciro / Sarno, Giuliana / Pacilio, Ida / Cianciulli, Agostino / Viviano, Monica / Iannelli, Giulia / Gazzillo, Erica / Feoli, Alessandra / Cipriano, Alessandra / Chini, Maria Giovanna / Castellano, Sabrina / Bifulco, Giuseppe / Sbardella, Gianluca

ChemMedChem

2024 , Seite(n) e202400139

Abstract: Protein arginine methyltransferase (PRMT) 4 (also known as coactivator-associated arginine methyltransferase 1; CARM1) is involved in a variety of biological processes and is considered as an emerging target class in oncology and other diseases. A ... ...

Abstract	Protein arginine methyltransferase (PRMT) 4 (also known as coactivator-associated arginine methyltransferase 1; CARM1) is involved in a variety of biological processes and is considered as an emerging target class in oncology and other diseases. A successful strategy to identify PRMT substrate-competitive inhibitors has been to exploit chemical scaffolds able to mimic the arginine substrate. (S)-Alanine amide moiety is a valuable arginine mimic for the development of potent and selective PRMT4 inhibitors; however, its high hydrophilicity led to derivatives with poor cellular outcomes. Here, we describe the development of PRMT4 inhibitors featuring a central pyrrole core and an alanine amide moiety. Rounds of optimization, aimed to increase lipophilicity and simultaneously preserve the inhibitory activity, produced derivatives that, despite good potency and physicochemical properties, did not achieve on-target effects in cells. On the other hand, masking the amino group with a NAD(P)H:quinone oxidoreductase 1 (NQO1)-responsive trigger group, led to prodrugs able to reduce arginine dimethylation of the PRMT4 substrates BRG1-associated factor 155 (BAF155). These results indicate that prodrug strategies can be successfully applied to alanine-amide containing PRMT4 inhibitors and provide an option to enable such compounds to achieve sufficiently high exposures in vivo.
Sprache	Englisch
Erscheinungsdatum	2024-05-16
Erscheinungsland	Germany
Dokumenttyp	Journal Article
ZDB-ID	2218496-X
ISSN	1860-7187 ; 1860-7179
ISSN (online)	1860-7187
ISSN	1860-7179
DOI	10.1002/cmdc.202400139
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Repositioning of Small Molecules through the Inverse Virtual Screening in silico Tool: Case of Benzothiazole-Based Inhibitors of Soluble Epoxide Hydrolase (sEH).

Gazzillo, Erica / Colarusso, Ester / Giordano, Assunta / Chini, Maria Giovanna / Potenza, Marianna / Hofstetter, Robert Klaus / Iorizzi, Maria / Werz, Oliver / Lauro, Gianluigi / Bifulco, Giuseppe

ChemPlusChem

2024 , Seite(n) e202400234

Abstract: Computational techniques accelerate drug discovery by identifying bioactive compounds for specific targets, optimizing molecules with moderate activity, or facilitating the repositioning of inactive items onto new targets. Among them, the Inverse Virtual ...

Abstract	Computational techniques accelerate drug discovery by identifying bioactive compounds for specific targets, optimizing molecules with moderate activity, or facilitating the repositioning of inactive items onto new targets. Among them, the Inverse Virtual Screening (IVS) approach is aimed at the evaluation of one or a small set of molecules against a panel of targets for addressing target identification. In this work, a focused library of benzothiazole-based compounds was re-investigated by IVS. Four items, originally synthesized and tested on bromodomain-containing protein 9 (BRD9) but yielding poor results, were critically re-analyzed, disclosing only a partial fit with 3D structure-based pharmacophore models, which, in the meanwhile, were developed for this target. Afterwards, these compounds were re-evaluated through IVS on a panel of proteins involved in inflammation and cancer, identifying soluble epoxide hydrolase (sEH) as a putative interacting target. Three items were subsequently confirmed as able to inhibit sEH activity, spanning from 70% up to 30% when tested at 10 μM. Finally, one benzothiazole-based compound emerged as the most promising inhibitor featuring an IC50 in the low micromolar range (IC50 = 6.62 ± 0.13 μM). Our data confirm IVS as a predictive tool for accelerating the target identification and repositioning processes.
Sprache	Englisch
Erscheinungsdatum	2024-05-16
Erscheinungsland	Germany
Dokumenttyp	Journal Article
ISSN	2192-6506
ISSN (online)	2192-6506
DOI	10.1002/cplu.202400234
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Accelerating the repurposing of FDA-approved drugs against coronavirus disease-19 (COVID-19).

De Vita, Simona / Chini, Maria Giovanna / Lauro, Gianluigi / Bifulco, Giuseppe

RSC advances

2020 Band 10, Heft 67, Seite(n) 40867–40875

Abstract: The recent release of the main protein structures belonging to SARS CoV-2, responsible for the coronavirus disease-19 (COVID-19), strongly pushed for identifying valuable drug treatments. With this aim, we show a repurposing study on FDA-approved drugs ... ...

Abstract	The recent release of the main protein structures belonging to SARS CoV-2, responsible for the coronavirus disease-19 (COVID-19), strongly pushed for identifying valuable drug treatments. With this aim, we show a repurposing study on FDA-approved drugs applying a new computational protocol and introducing a novel parameter called IVS
Sprache	Englisch
Erscheinungsdatum	2020-11-10
Erscheinungsland	England
Dokumenttyp	Journal Article
ISSN	2046-2069
ISSN (online)	2046-2069
DOI	10.1039/d0ra09010g
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Accelerating the repurposing of FDA-approved drugs against coronavirus disease-19 (COVID-19)

De Vita, Simona / Chini, Maria Giovanna / Lauro, Gianluigi / Bifulco, Giuseppe

RSC advances. 2020 Nov. 10, v. 10, no. 67

2020

Abstract	The recent release of the main protein structures belonging to SARS CoV-2, responsible for the coronavirus disease-19 (COVID-19), strongly pushed for identifying valuable drug treatments. With this aim, we show a repurposing study on FDA-approved drugs applying a new computational protocol and introducing a novel parameter called IVSᵣₐₜᵢₒ. Starting with a virtual screening against three SARS CoV-2 targets (main protease, papain-like protease, spike protein), the top-ranked molecules were reassessed combining the Inverse Virtual Screening novel approach and MM-GBSA calculations. Applying this protocol, a list of drugs was identified against the three investigated targets. Also, the top-ranked selected compounds on each target (rutin vs. main protease, velpatasvir vs. papain-like protease, lomitapide vs. spike protein) were further tested with molecular dynamics simulations to confirm the promising binding modes, obtaining encouraging results such as high stability of the complex during the simulation and a good protein–ligand interaction network involving some important residues of each target. Moreover, the recent outcomes highlighting the inhibitory activity of quercetin, a natural compound strictly related to rutin, on the SARS-CoV-2 main protease, strengthened the applicability of the proposed workflow.
Schlagwörter	Coronavirus infections ; Orthocoronavirinae ; drugs ; molecular dynamics ; protein structure ; proteinases ; protocols ; quercetin ; rutin ; screening
Sprache	Englisch
Erscheinungsverlauf	2020-1110
Umfang	p. 40867-40875.
Erscheinungsort	The Royal Society of Chemistry
Dokumenttyp	Artikel
Anmerkung	NAL-light
ISSN	2046-2069
DOI	10.1039/d0ra09010g
Datenquelle	NAL Katalog (AGRICOLA)

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