2015
Rino, Ragno; Flavio, Ballante; Adele, Pirolli; Richard B, Wickersham III; Alexandros, Patsilinakos; Stéphanie, Hesse; Enrico, Perspicace; Gilbert, Kirsch
In: Journal of Computer-Aided Molecular Design, 29 (8), pp. 757-776, 2015.
Abstract | Links | BibTeX | Tags: 3-D QSAutogrid/R, 3D QSAR, Ligand-Based Design, Molecular Docking, Molecular Modeling, Pharmacophoric Model, PLS, VEGFR-2
@article{Ragno2015,
title = {Vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors: development and validation of predictive 3-D QSAR models through extensive ligand-and structure-based approaches},
author = {Ragno Rino and Ballante Flavio and Pirolli Adele and Richard B, Wickersham III and Patsilinakos Alexandros and Hesse Stéphanie and Perspicace Enrico and Kirsch Gilbert},
editor = {Springer International Publishing},
url = {http://link.springer.com/article/10.1007%2Fs10822-015-9859-y},
doi = {10.1007/s10822-015-9859-y},
year = {2015},
date = {2015-07-21},
urldate = {2015-07-21},
journal = {Journal of Computer-Aided Molecular Design},
volume = {29},
number = {8},
pages = {757-776},
abstract = {Vascular endothelial growth factor receptor-2, (VEGFR-2), is a key element in angiogenesis, the process by which new blood vessels are formed, and is thus an important pharmaceutical target. Here, 3-D quantitative structure-activity relationship (3-D QSAR) were used to build a quantitative screening and pharmacophore model of the VEGFR-2 receptors for design of inhibitors with improved activities. Most of available experimental data information has been used as training set to derive optimized and fully cross-validated eight mono-probe and a multi-probe quantitative models. Notable is the use of 262 molecules, aligned following both structure-based and ligand-based protocols, as external test set confirming the 3-D QSAR models' predictive capability and their usefulness in design new VEGFR-2 inhibitors. From a survey on literature, this is the first generation of a wide-ranging computational medicinal chemistry application on VEGFR2 inhibitors. },
keywords = {3-D QSAutogrid/R, 3D QSAR, Ligand-Based Design, Molecular Docking, Molecular Modeling, Pharmacophoric Model, PLS, VEGFR-2},
pubstate = {published},
tppubtype = {article}
}
2014
Antonia, Caroli; Flavio, Ballante; Richard B, Wickersham III; Federico, Corelli; Rino, Ragno
Hsp90 Inhibitors, Part 2: Combining Ligand-Based and Structure-Based Approaches for Virtual Screening Application Journal Article
In: Journal of Chemical Information and Modeling, 54 (3), pp. 970-977, 2014.
Abstract | Links | BibTeX | Tags: 3-D QSAutogrid/R, 3D QSAR, HSP90, Ligand-Based Design, Molecular Docking, Molecular Modeling, MPGRS, Pharmacophoric Model, PLS, Virtual Screening
@article{Caroli2014,
title = {Hsp90 Inhibitors, Part 2: Combining Ligand-Based and Structure-Based Approaches for Virtual Screening Application},
author = { Caroli Antonia and Ballante Flavio and Richard B, Wickersham III and Corelli Federico and Ragno Rino},
editor = {American Chemical Society},
url = {http://pubs.acs.org/doi/abs/10.1021/ci400760a},
doi = {10.1021/ci400760a},
year = {2014},
date = {2014-03-04},
journal = {Journal of Chemical Information and Modeling},
volume = {54},
number = {3},
pages = {970-977},
abstract = {Hsp90 continues to be an important target for pharmaceutical discovery. In this project, virtual screening (VS) for novel Hsp90 inhibitors was performed using a combination of Autodock and Surflex-Sim (LB) scoring functions with the predictive ability of 3-D QSAR models, previously generated with the 3-D QSAutogrid/R procedure. Extensive validation of both structure-based (SB) and ligand-based (LB), through realignments and cross-alignments, allowed the definition of LB and SB alignment rules. The mixed LB/SB protocol was applied to virtually screen potential Hsp90 inhibitors from the NCI Diversity Set composed of 1785 compounds. A selected ensemble of 80 compounds were biologically tested. Among these molecules, preliminary data yielded four derivatives exhibiting IC50 values ranging between 18 and 63 μM as hits for a subsequent medicinal chemistry optimization procedure.},
keywords = {3-D QSAutogrid/R, 3D QSAR, HSP90, Ligand-Based Design, Molecular Docking, Molecular Modeling, MPGRS, Pharmacophoric Model, PLS, Virtual Screening},
pubstate = {published},
tppubtype = {article}
}
Flavio, Ballante; Antonia, Caroli; Richard B, Wickersham III; Rino, Ragno
Hsp90 inhibitors, part 1: definition of 3-D QSAutogrid/R models as a tool for virtual screening Journal Article
In: Journal of Chemical Information and Modeling, 54 (3), pp. 956-969, 2014.
Abstract | Links | BibTeX | Tags: 3-D QSAutogrid/R, 3D QSAR, HSP90, Ligand-Based Design, Molecular Docking, Pharmacophoric Model, PLS, Virtual Screening
@article{Ballante2014,
title = {Hsp90 inhibitors, part 1: definition of 3-D QSAutogrid/R models as a tool for virtual screening},
author = { Ballante Flavio and Caroli Antonia and Richard B, Wickersham III and Ragno Rino},
editor = {American Chemical Society},
url = {http://pubs.acs.org/doi/abs/10.1021/ci400759t},
doi = {10.1021/ci400759t},
year = {2014},
date = {2014-03-04},
journal = {Journal of Chemical Information and Modeling},
volume = {54},
number = {3},
pages = {956-969},
abstract = {The multichaperone heat shock protein (Hsp) 90 complex mediates the maturation and stability of a variety of oncogenic signaling proteins. For this reason, Hsp90 has emerged as a promising target for anticancer drug development. Herein, we describe a complete computational procedure for building several 3-D QSAR models used as a ligand-based (LB) component of a comprehensive ligand-based (LB) and structure-based (SB) virtual screening (VS) protocol to identify novel molecular scaffolds of Hsp90 inhibitors. By the application of the 3-D QSAutogrid/R method, eight SB PLS 3-D QSAR models were generated, leading to a final multiprobe (MP) 3-D QSAR pharmacophoric model capable of recognizing the most significant chemical features for Hsp90 inhibition. Both the monoprobe and multiprobe models were optimized, cross-validated, and tested against an external test set. The obtained statistical results confirmed the models as robust and predictive to be used in a subsequent VS.},
keywords = {3-D QSAutogrid/R, 3D QSAR, HSP90, Ligand-Based Design, Molecular Docking, Pharmacophoric Model, PLS, Virtual Screening},
pubstate = {published},
tppubtype = {article}
}
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}
}
2013
Flavio, Ballante; Giampiero, Tempera; Enzo, Agostinelli; Rino, Ragno
Amino Acids, 45 (3), 2013.
Abstract | Links | BibTeX | Tags: 3-D QSAutogrid/R, 3D QSAR, Biochemistry, BSAO, Molecular Docking, Molecular Modeling, MPGRS
@proceedings{Ballante2013,
title = {Computational strategies to design new highly potential BSAO polyamine substrates - Abstracts presented at the 13th International Congress on Amino acids, peptides and proteins},
author = { Ballante Flavio and Tempera Giampiero and Agostinelli Enzo and Ragno Rino},
editor = {Springer Vienna},
url = {http://download.springer.com/static/pdf/197/art%253A10.1007%252Fs00726-013-1540-y.pdf?originUrl=http%3A%2F%2Flink.springer.com%2Farticle%2F10.1007%2Fs00726-013-1540-y&token2=exp=1444353564~acl=%2Fstatic%2Fpdf%2F197%2Fart%25253A10.1007%25252Fs00726-013-1540-y.pdf%3ForiginUrl%3Dhttp%253A%252F%252Flink.springer.com%252Farticle%252F10.1007%252Fs00726-013-1540-y*~hmac=66a792a46e66a768bf3d1cb3234517395253a9cc6ae57d90e54f70fac98f81ed},
doi = {10.1007/s00726-013-1540-y},
year = {2013},
date = {2013-10-07},
volume = {45},
number = {3},
publisher = {Amino Acids},
series = {Abstracts presented at the 13th International Congress on Amino Acids, Peptides and Proteins},
abstract = {Natural polyamines putrescine, spermidine and spermine are ubiqui-
tous polycationic compounds present in significant amounts in nearly
every prokaryotic and eukaryotic cell type. Spermidine and spermine
primarily exist in aqueous solution at pH 7.4 as fully protonated
polycations. Such ubiquitous chemical entities play an important role
in cell growth and proliferation, in the synthesis of proteins and
nucleic acids, in both normal and cancer cells. Preliminary structure
based (SB) studies through the AutoDock suite were performed on 25
among natural polyamines and newly synthesized and biologically
assayed polyamine analogs in order to clarify their binding modes.
Further investigations through a combined approach of docking and
3-D QSAR and COMBINE procedures, named 3-D QSAutogrid/R
and COMBINEr respectively, are in due course to rationalize in a
multi-informative scenario the different activity profiles and derive a
useful pharmacophoric frame able to weight the different ligand-
residues interactions magnitudes. Such approach will be useful for the
development of novel compounds endowed of both higher potency
and selectivity. As future perspective, these molecules will be assayed
alone or in combination with BSAO on several cancer cells, with the
aim to evaluate their cytotoxic effects that could be taken into con-
sideration as new approach in anti-cancer therapy. Details and
methodologies will be reported.},
keywords = {3-D QSAutogrid/R, 3D QSAR, Biochemistry, BSAO, Molecular Docking, Molecular Modeling, MPGRS},
pubstate = {published},
tppubtype = {proceedings}
}
tous polycationic compounds present in significant amounts in nearly
every prokaryotic and eukaryotic cell type. Spermidine and spermine
primarily exist in aqueous solution at pH 7.4 as fully protonated
polycations. Such ubiquitous chemical entities play an important role
in cell growth and proliferation, in the synthesis of proteins and
nucleic acids, in both normal and cancer cells. Preliminary structure
based (SB) studies through the AutoDock suite were performed on 25
among natural polyamines and newly synthesized and biologically
assayed polyamine analogs in order to clarify their binding modes.
Further investigations through a combined approach of docking and
3-D QSAR and COMBINE procedures, named 3-D QSAutogrid/R
and COMBINEr respectively, are in due course to rationalize in a
multi-informative scenario the different activity profiles and derive a
useful pharmacophoric frame able to weight the different ligand-
residues interactions magnitudes. Such approach will be useful for the
development of novel compounds endowed of both higher potency
and selectivity. As future perspective, these molecules will be assayed
alone or in combination with BSAO on several cancer cells, with the
aim to evaluate their cytotoxic effects that could be taken into con-
sideration as new approach in anti-cancer therapy. Details and
methodologies will be reported.
Enrico, Perspicace; Valérie, Jouan-Hureaux; Rino, Ragno; Flavio, Ballante; Stefania, Sartini; Concettina, La Motta; Federico, Da Settimo; Binbin, Chen; Gilbert, Kirsch; Serge, Schneider; Béatrice, Faivre; Stéphanie, Hesse
In: European Journal of Medicinal Chemistry, 63 , pp. 765-781, 2013.
Abstract | Links | BibTeX | Tags: 3-D QSAutogrid/R, 3D QSAR, Biochemistry, HUVEC, Organic Chemistry, PLS, VEGFR-2
@article{Perspicace2013,
title = {Design, synthesis and biological evaluation of new classes of thieno [3, 2-d] pyrimidinone and thieno [1, 2, 3] triazine as inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2)},
author = { Perspicace Enrico and Jouan-Hureaux Valérie and Ragno Rino and Ballante Flavio and Sartini Stefania and La Motta Concettina and Da Settimo Federico and Chen Binbin and Kirsch Gilbert and Schneider Serge and Faivre Béatrice and Hesse Stéphanie},
editor = {Elsevier Masson},
url = {http://www.sciencedirect.com/science/article/pii/S0223523413001700},
doi = {10.1016/j.ejmech.2013.03.022},
year = {2013},
date = {2013-05-31},
journal = {European Journal of Medicinal Chemistry},
volume = {63},
pages = {765-781},
abstract = {Driven by a multidisciplinary approach combination (Structure-Based (SB) Three-Dimensional Quantitative Structure–Activity Relationships (3-D QSAR), molecular modeling, organic chemistry and various biological evaluations) here is reported the disclosure of new thienopyrimidines 1–3 as inhibitors of KDR activity and human umbilical vein endothelial cell (HUVEC) proliferation. More specifically, compound 2f represents a new lead compound that inhibits VEGFR-2 and HUVEC at μM concentration. Moreover by the mean of an endothelial cell tube formation in vitro model 2f tartaric acid salt proved to block angiogenesis of HUVEC at μM level.},
keywords = {3-D QSAutogrid/R, 3D QSAR, Biochemistry, HUVEC, Organic Chemistry, PLS, VEGFR-2},
pubstate = {published},
tppubtype = {article}
}
Laura, Friggeri; Flavio, Ballante; Rino, Ragno; Ira, Musmuca; Daniela, De Vita; Fabrizio, Manetti; Mariangela, Biava; Luigi, Scipione; Roberto, Di Santo; Roberta, Costi; Marta, Feroci; Silvano, Tortorella
In: Journal of Chemical Information and Modeling, 53 (6), pp. 1463-1474, 2013.
Abstract | Links | BibTeX | Tags: 3-D QSAutogrid/R, 3D QSAR, Ligand-Based Design, MPGRS, Organic Chemistry, Pharmacophoric Model, PLS, Tuberculosis
@article{Friggeri2013,
title = {Pharmacophore assessment through 3-D QSAR: Evaluation of the predictive ability on new derivatives by the application on a series of antitubercular agents},
author = { Friggeri Laura and Ballante Flavio and Ragno Rino and Musmuca Ira and De Vita Daniela and Manetti Fabrizio and Biava Mariangela and Scipione Luigi and Di Santo Roberto and Costi Roberta and Feroci Marta and Tortorella Silvano},
editor = {American Chemical Society},
url = {http://pubs.acs.org/doi/abs/10.1021/ci400132q},
doi = {10.1021/ci400132q},
year = {2013},
date = {2013-05-17},
journal = {Journal of Chemical Information and Modeling},
volume = {53},
number = {6},
pages = {1463-1474},
abstract = {Pharmacophoric mapping is a useful procedure to frame, especially when crystallographic receptor structures are unavailable as in ligand-based studies, the hypothetical site of interaction. In this study, 71 pyrrole derivatives active against M. tuberculosis were used to derive through a recent new 3-D QSAR protocol, 3-D QSAutogrid/R, several predictive 3-D QSAR models on compounds aligned by a previously reported pharmacophoric application. A final multiprobe (MP) 3-D QSAR model was then obtained configuring itself as a tool to derive pharmacophoric quantitative models. To stress the applicability of the described models, an external test set of unrelated and newly synthesized series of R-4-amino-3-isoxazolidinone derivatives found to be active at micromolar level against M. tuberculosis was used, and the predicted bioactivities were in good agreement with the experimental values. The 3-D QSAutogrid/R procedure proved to be able to correlate by a single multi-informative scenario the different activity molecular profiles thus confirming its usefulness in the rational drug design approach.},
keywords = {3-D QSAutogrid/R, 3D QSAR, Ligand-Based Design, MPGRS, Organic Chemistry, Pharmacophoric Model, PLS, Tuberculosis},
pubstate = {published},
tppubtype = {article}
}
2012
Flavio, Ballante; Rino, Ragno
3-D QSAutogrid/R: An Alternative Procedure To Build 3-D QSAR Models. Methodologies and Applications Journal Article
In: Journal of Chemical Information and Modeling, 52 (6), pp. 1674, 2012.
Abstract | Links | BibTeX | Tags: 3-D QSAutogrid/R, 3D QSAR, Chemoinformatics, Chemometrics, CoMFA, HCV NS5B, Molecular Modeling, MPGRS, Opioid-Receptor Antagonists, PLS
@article{Ballante2012,
title = {3-D QSAutogrid/R: An Alternative Procedure To Build 3-D QSAR Models. Methodologies and Applications},
author = { Ballante Flavio and Ragno Rino},
editor = {American Chemical Society},
url = {http://pubs.acs.org/doi/abs/10.1021/ci300123x},
doi = {10.1021/ci300123x},
year = {2012},
date = {2012-06-25},
journal = {Journal of Chemical Information and Modeling},
volume = {52},
number = {6},
pages = {1674},
abstract = {Since it first appeared in 1988 3-D QSAR has proved its potential in the field of drug design and activity prediction. Although thousands of citations now exist in 3-D QSAR, its development was rather slow with the majority of new 3-D QSAR applications just extensions of CoMFA. An alternative way to build 3-D QSAR models, based on an evolution of software, has been named 3-D QSAutogrid/R and has been developed to use only software freely available to academics. 3-D QSAutogrid/R covers all the main features of CoMFA and GRID/GOLPE with implementation by multiprobe/multiregion variable selection (MPGRS) that improves the simplification of interpretation of the 3-D QSAR map. The methodology is based on the integration of the molecular interaction fields as calculated by AutoGrid and the R statistical environment that can be easily coupled with many free graphical molecular interfaces such as UCSF-Chimera, AutoDock Tools, JMol, and others. The description of each R package is reported in detail, and, to assess its validity, 3-D QSAutogrid/R has been applied to three molecular data sets of which either CoMFA or GRID/GOLPE models were reported in order to compare the results. 3-D QSAutogrid/R has been used as the core engine to prepare more that 240 3-D QSAR models forming the very first 3-D QSAR server (www.3d-qsar.com) with its code freely available through R-Cran distribution.},
keywords = {3-D QSAutogrid/R, 3D QSAR, Chemoinformatics, Chemometrics, CoMFA, HCV NS5B, Molecular Modeling, MPGRS, Opioid-Receptor Antagonists, PLS},
pubstate = {published},
tppubtype = {article}
}