2020
Nencetti, Susanna; Cuffaro, Doretta; Nuti, Elisa; Ciccone, Lidia; Rossello, Armando; Fabbi, Marina; Ballante, Flavio; Ortore, Gabriella; Carbotti, Grazia; Campelli, Francesco; Banti, Irene; Gangemi, Rosaria; Marshall, Garland R.; Orlandini, Elisabetta
Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines Journal Article
In: Journal of Enzyme Inhibition and Medicinal Chemistry, 36 (1), pp. 34–47, 2020.
Abstract | Links | BibTeX | Tags: Biochemistry, HDAC, Molecular Docking, Molecular Modeling
@article{Nencetti2020,
title = {Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines},
author = {Susanna Nencetti and Doretta Cuffaro and Elisa Nuti and Lidia Ciccone and Armando Rossello and Marina Fabbi and Flavio Ballante and Gabriella Ortore and Grazia Carbotti and Francesco Campelli and Irene Banti and Rosaria Gangemi and Garland R. Marshall and Elisabetta Orlandini},
url = {https://www.tandfonline.com/doi/full/10.1080/14756366.2020.1835883},
doi = {10.1080/14756366.2020.1835883},
year = {2020},
date = {2020-10-26},
urldate = {2020-10-26},
journal = {Journal of Enzyme Inhibition and Medicinal Chemistry},
volume = {36},
number = {1},
pages = {34–47},
abstract = {Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treat-ment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have beenstudied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeuticagents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)a-minoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 byfluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular dock-ing. The most promising hit was the quinoline derivativeVS13, a nanomolar inhibitor of HDAC6, whichexhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability tomodify the mRNA levels of HDAC target genes similar to that of SAHA.},
keywords = {Biochemistry, HDAC, Molecular Docking, Molecular Modeling},
pubstate = {published},
tppubtype = {article}
}
2016
Reddy, D. Rajasekhar; Ballante, Flavio; Zhou, Nancy J.; Marshall, Garland R.
Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors Journal Article
In: European Journal of Medicinal Chemistry, 127 , pp. Pages 531–553, 2016.
Abstract | Links | BibTeX | Tags: Biochemistry, HDAC, Molecular Docking
@article{Reddy2016,
title = {Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors},
author = {D. Rajasekhar Reddy and Flavio Ballante and Nancy J. Zhou and Garland R. Marshall},
url = {http://www.sciencedirect.com/science/article/pii/S0223523416310388?np=y},
doi = {10.1016/j.ejmech.2016.12.032},
year = {2016},
date = {2016-12-16},
journal = {European Journal of Medicinal Chemistry},
volume = {127},
pages = {Pages 531–553},
abstract = {A comprehensive investigation was performed to identify new benzodiazepine (BZD) derivatives as potent and selective human lysine deacetylase inhibitors (hKDACis). A total of 108 BZD compounds were designed, synthesized and from that 104 compounds were biologically evaluated against human lysine deacetylases (hKDACs) 1, 3 and 8 (class I) and 6 (class IIb). The most active compounds showed mid-nanomolar potencies against hKDACs 1, 3 and 6 and micromolar activity against hKDAC8, while a promising compound (6q) showed selectivity towards hKDAC3 among the different enzyme isoforms. An hKDAC6 homology model, refined by molecular dynamics simulation was generated, and molecular docking studies performed to rationalize the dominant ligand-residue interactions as well as to define structure-activity-relationships. Experimental results confirmed the usefulness of the benzodiazepine moiety as capping group when pursuing hKDAC isoform-selectivity inhibition, suggesting its continued use when designing new hKDACis.},
keywords = {Biochemistry, HDAC, Molecular Docking},
pubstate = {published},
tppubtype = {article}
}
2015
Damodara, Reddy Nandarapu; Flavio, Ballante; Timothy, Chuang; Adele, Pirolli; Biagina, Marrocco; Garland R, Marshall
Design and Synthesis of Simplified Largazole Analogs as Isoform-Selective Human Lysine Deacetylase Inhibitors Journal Article
In: Journal of Medicinal Chemistry, in press , 2015.
Abstract | Links | BibTeX | Tags: Biochemistry, HDAC, Molecular Docking, Organic Chemistry
@article{Reddy2015,
title = {Design and Synthesis of Simplified Largazole Analogs as Isoform-Selective Human Lysine Deacetylase Inhibitors},
author = {Reddy Nandarapu Damodara and Ballante Flavio and Chuang Timothy and Pirolli Adele and Marrocco Biagina and Garland R, Marshall },
editor = {American Chemical Society},
url = {http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01632},
doi = {10.1021/acs.jmedchem.5b01632},
year = {2015},
date = {2015-12-17},
journal = {Journal of Medicinal Chemistry},
volume = {in press},
abstract = {Selective inhibition of KDAC6isoforms while maintaining potency remains a challenge. Using the largazole macrocyclic depsipeptide structure as a starting point for developing new KDACIs with increased selectivity, a combination of four different simplified largazole analog (SLA) scaffolds with diverse zinc6binding groups (for a total of 60
compounds) were designed, synthesized and evaluated against class I KDACs 1, 3 and 8, and class II KDAC6. Experimental evidence as well as molecular docking poses converged to establish the cyclic tetrapeptides (CTPs) as the primary determinant of both potency and selectivity, by influencing the correct alignment of the zinc6binding
group in the KDAC active site, providing a further basis for developing new KDACIs of higher isoform selectivity and potency. },
keywords = {Biochemistry, HDAC, Molecular Docking, Organic Chemistry},
pubstate = {published},
tppubtype = {article}
}
compounds) were designed, synthesized and evaluated against class I KDACs 1, 3 and 8, and class II KDAC6. Experimental evidence as well as molecular docking poses converged to establish the cyclic tetrapeptides (CTPs) as the primary determinant of both potency and selectivity, by influencing the correct alignment of the zinc6binding
group in the KDAC active site, providing a further basis for developing new KDACIs of higher isoform selectivity and potency.
2014
Flavio, Ballante
Application of Medicinal Chemistry Methods on Different Classes of Drugs PhD Thesis
Sapienza University of Rome, 2014.
Abstract | Links | BibTeX | Tags: 3-D QSAutogrid/R, 3D QSAR, Biochemistry, BSAO, Chemoinformatics, Chemometrics, COMBINEr, CoMFA, DABO, DockAccessor, Docking Assessment, HCV NS5B, HDAC, HIV-1, HIV-RT, HSP90, HUVEC, Ligand-Based Design, Molecular Docking, Molecular Modeling, MPGRS, NNRTIs, Opioid-Receptor Antagonists, Organic Chemistry, Pharmacophoric Model, PLS, Tuberculosis, VEGFR-2, Virtual Screening
@phdthesis{Ballante2014b,
title = {Application of Medicinal Chemistry Methods on Different Classes of Drugs},
author = { Ballante Flavio},
editor = {PADIS},
url = {http://hdl.handle.net/11573/918780 },
year = {2014},
date = {2014-01-27},
address = {Department of Chemistry and Tecnology of Drugs},
school = {Sapienza University of Rome},
abstract = {The present doctoral thesis is the result of the work carried out during the three years of my PhD scholarship at the Rome Center for Molecular Design laboratory (RCMD, Department of Chemistry and Drug Technologies, Sapienza University of Rome), under the supervision of Prof. Rino Ragno. The research activity was focused mainly on the design, optimization and application of computational strategies to derive quantitative structure-activity relationships (QSAR, 3-D QSAR, and COMBINE) on different molecular classes of current interest, such as: opioid receptor antagonists (OPAs), Hepatitis C Virus NS5B-Polymerase Inhibitors (NS5B-NNIs), Hystone Deacetylase Inhibitors (HDACIs), Anti- tubercular agents, vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors, HSP90 inhibitors, HIV-1 reverse transcriptase inhibitors (NNRTIs), Bovine Serum Amine Oxidase (BSAO) substrates, etc... Moreover two research periods abroad were performed: the first framed in a LLP Erasmus program collaboration, was conducted for six months at the Laboratoire d'Ingénierie et Moléculaire Pharmacologique Biochimie (LIMBP) of the Université de Lorraine Metz (France), directed by Prof. Gilbert Kirsch, and characterized by the application of organic synthesis to obtain new thienopyrimidinone derivatives as potential inhibitors of vascular endothelial growth factor receptor-2 (VEGFR-2); the second took place, for three months, at the Department of Biochemistry and Molecular Biophysics in Washington University School of Medicine in Saint Louis (MO, USA), under the supervision of Prof. Garland R. Marshall, investigating the activity profile of new Histone Deacetylases (HDACs) inhibitors by the application of the Mobility Shift Assay Technology. Main purpose of this doctoral thesis is to highlight the activities carried out in the different research projects, the applied methodologies and the obtained results. The text starts describing those studies whose results were published in scientific journals (chapters I-VI): the author decided to omit some procedural details, completely reported in the published papers, that would make the text too long, tedious and redundant; therefore readers who want to delve these aspects can also refer to Chapter XII in which is possible to read the original papers; on the contrary for studies that have not yet been published, as those characterizing the Chapters VII and VIII, discussion is adequately detailed. Chapters IX and X report the scientific activities carried out in France and in USA respectively; Chapter XI summarizes all the scientific activities accomplished during the entire PhD course, whereas Chapter XII, as mentioned, contains the published articles.},
keywords = {3-D QSAutogrid/R, 3D QSAR, Biochemistry, BSAO, Chemoinformatics, Chemometrics, COMBINEr, CoMFA, DABO, DockAccessor, Docking Assessment, HCV NS5B, HDAC, HIV-1, HIV-RT, HSP90, HUVEC, Ligand-Based Design, Molecular Docking, Molecular Modeling, MPGRS, NNRTIs, Opioid-Receptor Antagonists, Organic Chemistry, Pharmacophoric Model, PLS, Tuberculosis, VEGFR-2, Virtual Screening},
pubstate = {published},
tppubtype = {phdthesis}
}
2012
Laura, Silvestri; Flavio, Ballante; Antonello, Mai; Garland R, Marshall; Rino, Ragno
Histone Deacetylase Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction Journal Article
In: Journal of Chemical Information and Modeling, 52 (8), pp. 2215-2235, 2012.
Abstract | Links | BibTeX | Tags: 3D QSAR, COMBINEr, HDAC, Molecular Docking, Molecular Modeling, PLS
@article{Silvestri2012,
title = {Histone Deacetylase Inhibitors: Structure-Based Modeling and Isoform-Selectivity Prediction},
author = { Silvestri Laura and Ballante Flavio and Mai Antonello and Garland R, Marshall and Ragno Rino},
editor = {American Chemical Society},
url = {http://pubs.acs.org/doi/abs/10.1021/ci300160y},
doi = {10.1021/ci300160y},
year = {2012},
date = {2012-07-19},
journal = {Journal of Chemical Information and Modeling},
volume = { 52},
number = {8},
pages = {2215-2235},
abstract = {An enhanced version of comparative binding energy (COMBINE) analysis, named COMBINEr, based on both ligand-based and structure-based alignments has been used to build several 3-D QSAR models for the eleven human zinc-based histone deacetylases (HDACs). When faced with an abundance of data from diverse structure–activity sources, choosing the best paradigm for an integrative analysis is difficult. A common example from studies on enzyme–inhibitors is the abundance of crystal structures characterized by diverse ligands complexed with different enzyme isoforms. A novel comprehensive tool for data mining on such inhomogeneous set of structure–activity data was developed based on the original approach of Ortiz, Gago, and Wade, and applied to predict HDAC inhibitors’ isoform selectivity. The COMBINEr approach (apart from the AMBER programs) has been developed to use only software freely available to academics.},
keywords = {3D QSAR, COMBINEr, HDAC, Molecular Docking, Molecular Modeling, PLS},
pubstate = {published},
tppubtype = {article}
}