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Article ; Online: Pliability in the m

Cazzanelli, Giulia / Dalle Vedove, Andrea / Spagnolli, Giovanni / Terruzzi, Luca / Colasurdo, Enrica / Boldrini, Alberto / Patsilinakos, Alexandros / Sturlese, Mattia / Grottesi, Alessandro / Biasini, Emiliano / Provenzani, Alessandro / Quattrone, Alessandro / Lolli, Graziano

Journal of chemical information and modeling

2024 Volume 64, Issue 5, Page(s) 1682–1690

Abstract: Epitranscriptomic mRNA modifications affect gene expression, with their altered balance detected in various cancers. YTHDF proteins contain the YTH reader domain recognizing the ... ...

Abstract	Epitranscriptomic mRNA modifications affect gene expression, with their altered balance detected in various cancers. YTHDF proteins contain the YTH reader domain recognizing the m
MeSH term(s)	RNA-Binding Proteins/chemistry ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Pliability ; RNA, Messenger/chemistry ; RNA, Messenger/metabolism ; Molecular Conformation
Chemical Substances	RNA-Binding Proteins ; RNA, Messenger
Language	English
Publishing date	2024-02-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.4c00051
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Article ; Online: Identification of a BAZ2A Bromodomain Hit Compound by Fragment Joining.

Dalle Vedove, Andrea / Cazzanelli, Giulia / Corsi, Jessica / Sedykh, Maria / D'Agostino, Vito Giuseppe / Caflisch, Amedeo / Lolli, Graziano

ACS bio & med chem Au

2021 Volume 1, Issue 1, Page(s) 5–10

Abstract: The bromodomains of BAZ2A and BAZ2B (bromodomain adjacent to zinc finger domain proteins 2) are among the most hard to drug of the 61 human bromodomains. While little is known about the role of BAZ2B, there is strong evidence for the opportunity of ... ...

Abstract	The bromodomains of BAZ2A and BAZ2B (bromodomain adjacent to zinc finger domain proteins 2) are among the most hard to drug of the 61 human bromodomains. While little is known about the role of BAZ2B, there is strong evidence for the opportunity of targeting BAZ2A in various cancers. Here, a benzimidazole-triazole fragment that binds to the BAZ2A acetyl lysine pocket was identified by a molecular docking campaign and validated by competitive binding assays and X-ray crystallography. Another ligand was observed in close proximity by soaking experiments using the BAZ2A bromodomain preincubated with the benzimidazole-triazole fragment. The crystal structure of BAZ2A with the two ligands was employed to design a few benzimidazole-triazole derivatives with increased affinity. We also present the engineering of a BAZ2A bromodomain mutant for consistent, high-resolution crystallographic studies.
Language	English
Publishing date	2021-07-07
Publishing country	United States
Document type	Journal Article
ISSN	2694-2437
ISSN (online)	2694-2437
DOI	10.1021/acsbiomedchemau.1c00016
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Article: Biochemical and cellular mechanism of protein kinase CK2 inhibition by deceptive curcumin

Cozza, Giorgio / Zonta, Francesca / Dalle Vedove, Andrea / Venerando, Andrea / Dall'Acqua, Stefano / Battistutta, Roberto / Ruzzene, Maria / Lolli, Graziano

FEBS journal. 2020 May, v. 287, no. 9

2020

Abstract: Protein kinase CK2 is an antiapoptotic cancer‐sustaining protein. Curcumin, reported previously as a CK2 inhibitor, is too bulky to be accommodated in the CK2 active site and rapidly degrades in solution generating various ATP‐mimetic inhibitors; with a ... ...

Abstract	Protein kinase CK2 is an antiapoptotic cancer‐sustaining protein. Curcumin, reported previously as a CK2 inhibitor, is too bulky to be accommodated in the CK2 active site and rapidly degrades in solution generating various ATP‐mimetic inhibitors; with a detailed comparative analysis, by means of both protein crystallography and enzymatic inhibition, ferulic acid was identified as the principal curcumin degradation product responsible for CK2 inhibition. The other curcumin derivatives vanillin, feruloylmethane and coniferyl aldehyde are weaker CK2 inhibitors. The high instability of curcumin in standard buffered solutions flags this compound, which is included in many commercial libraries, as a possible source of misleading interpretations, as was the case for CK2. Ferulic acid does not show any cytotoxicity and any inhibition of cellular CK2, due to its poor cellular permeability. However, curcumin acts as a prodrug in the cellular context, by generating its degradation products inside the treated cells, thus rescuing CK2 inhibition and consequently inducing cell death. Through the intracellular release of its degradation products, curcumin is expected to affect various target families; here, we identify the first bromodomain of BRD4 as a new target for those compounds. DATABASE: Structural data are available in the PDB database under the accession numbers 6HOP (CK2α/curcumin), 6HOQ (CK2α/ferulic acid), 6HOR (CK2α/feruloylmethane), 6HOT (CK2α/ferulic aldehyde), 6HOU (CK2α/vanillin) and 6HOV (BRD4/ferulic acid).
Keywords	active sites ; cell death ; crystallography ; curcumin ; cytotoxicity ; databases ; enzyme inhibition ; ferulic acid ; permeability ; protein kinases ; vanillin
Language	English
Dates of publication	2020-05
Size	p. 1850-1864.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	NAL-AP-2-clean ; JOURNAL ARTICLE
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.15111
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Discovery of Inhibitors of Four Bromodomains by Fragment-Anchored Ligand Docking.

Marchand, Jean-Rémy / Dalle Vedove, Andrea / Lolli, Graziano / Caflisch, Amedeo

Journal of chemical information and modeling

2017 Volume 57, Issue 10, Page(s) 2584–2597

Abstract: The high-throughput docking protocol called ALTA-VS (anchor-based library tailoring approach for virtual screening) was developed in 2005 for the efficient in silico screening of large libraries of compounds by preselection of only those molecules that ... ...

Abstract	The high-throughput docking protocol called ALTA-VS (anchor-based library tailoring approach for virtual screening) was developed in 2005 for the efficient in silico screening of large libraries of compounds by preselection of only those molecules that have optimal fragments (anchors) for the protein target. Here we present an updated version of ALTA-VS with a broader range of potential applications. The evaluation of binding energy makes use of a classical force field with implicit solvent in the continuum dielectric approximation. In about 2 days per protein target on a 96-core compute cluster (equipped with Xeon E3-1280 quad core processors at 2.5 GHz), the screening of a library of nearly 77 000 diverse molecules with the updated ALTA-VS protocol has resulted in the identification of 19, 3, 3, and 2 μM inhibitors of the human bromodomains ATAD2, BAZ2B, BRD4(1), and CREBBP, respectively. The success ratio (i.e., number of actives in a competition binding assay in vitro divided by the number of compounds tested) ranges from 8% to 13% in dose-response measurements. The poses predicted by fragment-based docking for the three ligands of the BAZ2B bromodomain were confirmed by protein X-ray crystallography.
MeSH term(s)	Binding Sites ; Drug Discovery ; Histone Chaperones ; Humans ; Ligands ; Models, Biological ; Molecular Docking Simulation ; Nuclear Proteins/antagonists & inhibitors ; Nuclear Proteins/chemistry ; Peptide Fragments/chemistry ; Protein Domains ; Small Molecule Libraries ; Water/chemistry
Chemical Substances	Histone Chaperones ; Ligands ; Nuclear Proteins ; Peptide Fragments ; Small Molecule Libraries ; Water (059QF0KO0R) ; BRD1 protein, human (EC 2.3.1.48)
Language	English
Publishing date	2017-09-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.7b00336
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Article: Identification of a BAZ2A-Bromodomain Hit Compound by Fragment Growing.

Dalle Vedove, Andrea / Cazzanelli, Giulia / Batiste, Laurent / Marchand, Jean-Rémy / Spiliotopoulos, Dimitrios / Corsi, Jessica / D'Agostino, Vito Giuseppe / Caflisch, Amedeo / Lolli, Graziano

ACS medicinal chemistry letters

2022 Volume 13, Issue 9, Page(s) 1434–1443

Abstract: BAZ2A is an epigenetic regulator affecting transcription of ribosomal RNA. It is overexpressed in aggressive and recurrent prostate cancer, promoting cellular migration. Its bromodomain is characterized by a shallow and difficult-to-drug pocket. Here, we ...

Abstract	BAZ2A is an epigenetic regulator affecting transcription of ribosomal RNA. It is overexpressed in aggressive and recurrent prostate cancer, promoting cellular migration. Its bromodomain is characterized by a shallow and difficult-to-drug pocket. Here, we describe a structure-based fragment-growing campaign for the identification of ligands of the BAZ2A bromodomain. By combining docking, competition binding assays, and protein crystallography, we have extensively explored the interactions of the ligands with the rim of the binding pocket, and in particular ionic interactions with the side chain of Glu1820, which is unique to BAZ2A. We present 23 high-resolution crystal structures of the holo BAZ2A bromodomain and analyze common bromodomain/ligand motifs and favorable intraligand interactions. Binding of some of the compounds is enantiospecific, with affinity in the low micromolar range. The most potent ligand has an equilibrium dissociation constant of 7 μM and a good selectivity over the paralog BAZ2B bromodomain.
Language	English
Publishing date	2022-08-03
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.2c00173
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Article ; Online: Biochemical and cellular mechanism of protein kinase CK2 inhibition by deceptive curcumin.

Cozza, Giorgio / Zonta, Francesca / Dalle Vedove, Andrea / Venerando, Andrea / Dall'Acqua, Stefano / Battistutta, Roberto / Ruzzene, Maria / Lolli, Graziano

The FEBS journal

2019 Volume 287, Issue 9, Page(s) 1850–1864

Abstract: Protein kinase CK2 is an antiapoptotic cancer-sustaining protein. Curcumin, reported previously as a CK2 inhibitor, is too bulky to be accommodated in the CK2 active site and rapidly degrades in solution generating various ATP-mimetic inhibitors; with a ... ...

Abstract	Protein kinase CK2 is an antiapoptotic cancer-sustaining protein. Curcumin, reported previously as a CK2 inhibitor, is too bulky to be accommodated in the CK2 active site and rapidly degrades in solution generating various ATP-mimetic inhibitors; with a detailed comparative analysis, by means of both protein crystallography and enzymatic inhibition, ferulic acid was identified as the principal curcumin degradation product responsible for CK2 inhibition. The other curcumin derivatives vanillin, feruloylmethane and coniferyl aldehyde are weaker CK2 inhibitors. The high instability of curcumin in standard buffered solutions flags this compound, which is included in many commercial libraries, as a possible source of misleading interpretations, as was the case for CK2. Ferulic acid does not show any cytotoxicity and any inhibition of cellular CK2, due to its poor cellular permeability. However, curcumin acts as a prodrug in the cellular context, by generating its degradation products inside the treated cells, thus rescuing CK2 inhibition and consequently inducing cell death. Through the intracellular release of its degradation products, curcumin is expected to affect various target families; here, we identify the first bromodomain of BRD4 as a new target for those compounds. DATABASE: Structural data are available in the PDB database under the accession numbers 6HOP (CK2α/curcumin), 6HOQ (CK2α/ferulic acid), 6HOR (CK2α/feruloylmethane), 6HOT (CK2α/ferulic aldehyde), 6HOU (CK2α/vanillin) and 6HOV (BRD4/ferulic acid).
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Casein Kinase II/antagonists & inhibitors ; Casein Kinase II/chemistry ; Casein Kinase II/metabolism ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Curcumin/chemistry ; Curcumin/pharmacology ; Drug Screening Assays, Antitumor ; Humans ; Models, Molecular ; Prodrugs/chemistry ; Prodrugs/pharmacology ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology
Chemical Substances	Antineoplastic Agents ; Prodrugs ; Protein Kinase Inhibitors ; Casein Kinase II (EC 2.7.11.1) ; Curcumin (IT942ZTH98)
Language	English
Publishing date	2019-11-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.15111
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Article ; Online: Molecular dynamics simulations provide insights into the substrate specificity of FAOX family members.

Rigoldi, Federica / Spero, Ludovica / Dalle Vedove, Andrea / Redaelli, Alberto / Parisini, Emilio / Gautieri, Alfonso

Molecular bioSystems

2016 Volume 12, Issue 8, Page(s) 2622–2633

Abstract: Enzymatic assays based on Fructosyl Amino Acid Oxidases (FAOX) represent a potential, rapid and economical strategy to measure glycated hemoglobin (HbA1c), which is in turn a reliable method to monitor the insurgence and the development of diabetes ... ...

Abstract	Enzymatic assays based on Fructosyl Amino Acid Oxidases (FAOX) represent a potential, rapid and economical strategy to measure glycated hemoglobin (HbA1c), which is in turn a reliable method to monitor the insurgence and the development of diabetes mellitus. However, the engineering of naturally occurring FAOX to specifically recognize fructosyl-valine (the glycated N-terminal residue of HbA1c) has been hindered by the paucity of information on the tridimensional structures and catalytic residues of the different FAOX that exist in nature, and in general on the molecular mechanisms that regulate specificity in this class of enzymes. In this study, we use molecular dynamics simulations and advanced modeling techniques to investigate five different relevant wild-type FAOX (Amadoriase I, Amadoriase II, PnFPOX, FPOX-E and N1-1-FAOD) in order to elucidate the molecular mechanisms that drive their specificity towards polar and nonpolar substrates. Specifically, we compare these five different FAOX in terms of overall folding, ligand entry tunnels, ligand binding residues and ligand binding energies. Our work will contribute to future enzyme structure modifications aimed at the rational design of novel biosensors for the monitoring of blood glucose levels.
MeSH term(s)	Amino Acid Oxidoreductases/chemistry ; Amino Acid Oxidoreductases/classification ; Amino Acid Oxidoreductases/genetics ; Amino Acid Oxidoreductases/metabolism ; Amino Acid Sequence ; Conserved Sequence ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Ligands ; Molecular Conformation ; Molecular Dynamics Simulation ; Multigene Family ; Phylogeny ; Salts/chemistry ; Structure-Activity Relationship ; Substrate Specificity
Chemical Substances	Ligands ; Salts ; Amino Acid Oxidoreductases (EC 1.4.-) ; amadoriase (EC 1.5.3.-)
Language	English
Publishing date	2016-07-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2188635-0
ISSN	1742-2051 ; 1742-206X
ISSN (online)	1742-2051
ISSN	1742-206X
DOI	10.1039/c6mb00405a
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Article ; Online: Crystal structure of the deglycating enzyme Amadoriase I in its free form and substrate-bound complex.

Rigoldi, Federica / Gautieri, Alfonso / Dalle Vedove, Andrea / Lucarelli, Anna Paola / Vesentini, Simone / Parisini, Emilio

Proteins

2016 Volume 84, Issue 6, Page(s) 744–758

Abstract: Amadoriases, also known as fructosyl amine oxidases (FAOX), are enzymes that catalyze the de-glycosylation of fructosyl amino acids. As such, they are excellent candidates for the development of enzyme-based diagnostic and therapeutic tools against age- ... ...

Abstract	Amadoriases, also known as fructosyl amine oxidases (FAOX), are enzymes that catalyze the de-glycosylation of fructosyl amino acids. As such, they are excellent candidates for the development of enzyme-based diagnostic and therapeutic tools against age- and diabetes-induced protein glycation. However, mostly because of the lack of a complete structural characterization of the different members of the family, the molecular bases of their substrate specificity have yet to be fully understood. The high resolution crystal structures of the free and the substrate-bound form of Amadoriase I shown herein allow for the identification of key structural features that account for the diverse substrate specificity shown by this class of enzymes. This is of particular importance in the context of the rather limited and partially incomplete structural information that has so far been available in the literature on the members of the FAOX family. Moreover, using molecular dynamics simulations, we describe the tunnel conformation and the free energy profile experienced by the ligand in going from bulk water to the catalytic cavity, showing the presence of four gating helices/loops, followed by an "L-shaped" narrow cavity. In summary, the tridimensional architecture of Amadoriase I presented herein provides a reference structural framework for the design of novel enzymes for diabetes monitoring and protein deglycation. Proteins 2016; 84:744-758. © 2016 Wiley Periodicals, Inc.
MeSH term(s)	Amino Acid Oxidoreductases/chemistry ; Amino Acid Oxidoreductases/metabolism ; Amino Acid Sequence ; Aspergillus fumigatus/chemistry ; Aspergillus fumigatus/enzymology ; Aspergillus fumigatus/metabolism ; Crystallography, X-Ray ; Lysine/analogs & derivatives ; Lysine/metabolism ; Models, Molecular ; Protein Binding ; Protein Conformation ; Sequence Alignment ; Substrate Specificity ; Thermodynamics
Chemical Substances	fructosyl-lysine (21291-40-7) ; Amino Acid Oxidoreductases (EC 1.4.-) ; amadoriase (EC 1.5.3.-) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	806683-8
ISSN	1097-0134 ; 0887-3585
ISSN (online)	1097-0134
ISSN	0887-3585
DOI	10.1002/prot.25015
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Article ; Online: Structural Analysis of Small-Molecule Binding to the BAZ2A and BAZ2B Bromodomains.

Dalle Vedove, Andrea / Spiliotopoulos, Dimitrios / D'Agostino, Vito G / Marchand, Jean-Rémy / Unzue, Andrea / Nevado, Cristina / Lolli, Graziano / Caflisch, Amedeo

ChemMedChem

2018 Volume 13, Issue 14, Page(s) 1479–1487

Abstract: The bromodomain-containing protein BAZ2A is a validated target in prostate cancer research, whereas the function of its paralogue BAZ2B is still undefined. The bromodomains of BAZ2A and BAZ2B have a similar binding site for their natural ligand, the ... ...

Abstract	The bromodomain-containing protein BAZ2A is a validated target in prostate cancer research, whereas the function of its paralogue BAZ2B is still undefined. The bromodomains of BAZ2A and BAZ2B have a similar binding site for their natural ligand, the acetylated lysine side chain. Here, we present an analysis of the binding modes of eight compounds belonging to three distinct chemical classes. For all compounds, the moiety mimicking the natural ligand engages in essentially identical interactions in the BAZ2A and BAZ2B bromodomains. In contrast, the rest of the molecule is partially solvent-exposed and adopts different orientations with different interactions in the two bromodomains. Some of these differences could be exploited for designing inhibitors with selectivity within the BAZ2 bromodomain subfamily.
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Chromosomal Proteins, Non-Histone/chemistry ; Chromosomal Proteins, Non-Histone/metabolism ; Crystallography, X-Ray ; Drug Discovery ; Humans ; Ligands ; Male ; Molecular Docking Simulation ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/metabolism ; Protein Binding ; Protein Domains/drug effects ; Proteins/chemistry ; Proteins/metabolism ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology
Chemical Substances	Antineoplastic Agents ; BAZ2A protein, human ; BAZ2B protein, human ; Chromosomal Proteins, Non-Histone ; Ligands ; Proteins ; Small Molecule Libraries
Language	English
Publishing date	2018-06-21
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2218496-X
ISSN	1860-7187 ; 1860-7179
ISSN (online)	1860-7187
ISSN	1860-7179
DOI	10.1002/cmdc.201800234
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Article ; Online: A novel class of selective CK2 inhibitors targeting its open hinge conformation.

Dalle Vedove, Andrea / Zonta, Francesca / Zanforlin, Enrico / Demitri, Nicola / Ribaudo, Giovanni / Cazzanelli, Giulia / Ongaro, Alberto / Sarno, Stefania / Zagotto, Giuseppe / Battistutta, Roberto / Ruzzene, Maria / Lolli, Graziano

European journal of medicinal chemistry

2020 Volume 195, Page(s) 112267

Abstract: Protein kinase CK2 sustains cancer growth, especially in hematological malignancies. Its inhibitor SRPIN803, based on a 6-methylene-5-imino-1,3,4-thiadiazolopyrimidin-7-one scaffold, showed notable specificity. Our synthesis of the initially proposed ... ...

Abstract	Protein kinase CK2 sustains cancer growth, especially in hematological malignancies. Its inhibitor SRPIN803, based on a 6-methylene-5-imino-1,3,4-thiadiazolopyrimidin-7-one scaffold, showed notable specificity. Our synthesis of the initially proposed SRPIN803 resulted in its constitutional isomer SRPIN803-revised, where the 2-cyano-2-propenamide group does not cyclise and fuse to the thiadiazole ring. Its crystallographic structure in complex with CK2α identifies the structural determinants of the reported specificity. SRPIN803-revised explores the CK2 open hinge conformation, extremely rare among kinases, also interacting with side chains from this region. Its optimization lead to the more potent compound 4, which inhibits endocellular CK2, significantly affects viability of tumour cells and shows remarkable selectivity on a panel of 320 kinases.
MeSH term(s)	Casein Kinase II/antagonists & inhibitors ; Casein Kinase II/chemistry ; Casein Kinase II/metabolism ; Drug Design ; Humans ; Jurkat Cells ; Molecular Docking Simulation ; Protein Conformation ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/metabolism ; Protein Kinase Inhibitors/pharmacology ; Pyrimidinones/chemistry ; Pyrimidinones/metabolism ; Pyrimidinones/pharmacology ; Structure-Activity Relationship ; Thiadiazoles/chemistry ; Thiadiazoles/metabolism ; Thiadiazoles/pharmacology
Chemical Substances	Protein Kinase Inhibitors ; Pyrimidinones ; SRPIN803 ; Thiadiazoles ; Casein Kinase II (EC 2.7.11.1)
Language	English
Publishing date	2020-03-25
Publishing country	France
Document type	Journal Article
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2020.112267
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