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  • 1.
    Ballante, Flavio
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Protein-Ligand Docking in Drug Design: Performance Assessment and Binding-Pose Selection2018In: Rational Drug Design: Methods and Protocols / [ed] Thomas Mavromoustakos; Tahsin F. Kellici, New York, NY: Humana Press, 2018, p. 67-88Chapter in book (Refereed)
    Abstract [en]

    Main goal in drug discovery is the identification of drug-like compounds capable to modulate specific biological targets. Thus, the prediction of reliable binding poses of candidate ligands, through molecular docking simulations, represents a key step to be pursued in structure-based drug design (SBDD). Since the increasing number of resolved three-dimensional ligand-protein structures, together with the expansion of computational power and software development, the comprehensive and systematic use of experimental data can be proficiently employed to validate the docking performance. This allows to select and refine the protocol to adopt when predicting the binding pose of trial compounds in a target. Given the availability of multiple docking software, a comparative docking assessment in an early research stage represents a must-use step to minimize fails in molecular modeling. This chapter describes how to perform a docking assessment, using freely available tools, in a semiautomated fashion.

  • 2.
    Ballante, Flavio
    et al.
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P. le A. Moro 5, 00185 Roma, Italy.
    Caroli, Antonia
    Department of Physics, Sapienza Universita ̀ di Roma, P.le Aldo Moro 5, 00185, Roma, Italy.
    Wickersham, Richard B
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Roma, Italy; Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
    Ragno, Rino
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Roma, Italy.
    Hsp90 inhibitors, part 1: definition of 3-D QSAutogrid/R models as a tool for virtual screening.2014In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 54, no 3, p. 956-69Article in journal (Refereed)
    Abstract [en]

    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.

  • 3.
    Ballante, Flavio
    et al.
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
    Marshall, Garland R
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
    An Automated Strategy for Binding-Pose Selection and Docking Assessment in Structure-Based Drug Design.2016In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 56, no 1, p. 54-72Article in journal (Refereed)
    Abstract [en]

    Molecular docking is a widely used technique in drug design to predict the binding pose of a candidate compound in a defined therapeutic target. Numerous docking protocols are available, each characterized by different search methods and scoring functions, thus providing variable predictive capability on a same ligand-protein system. To validate a docking protocol, it is necessary to determine a priori the ability to reproduce the experimental binding pose (i.e., by determining the docking accuracy (DA)) in order to select the most appropriate docking procedure and thus estimate the rate of success in docking novel compounds. As common docking programs use generally different root-mean-square deviation (RMSD) formulas, scoring functions, and format results, it is both difficult and time-consuming to consistently determine and compare their predictive capabilities in order to identify the best protocol to use for the target of interest and to extrapolate the binding poses (i.e., best-docked (BD), best-cluster (BC), and best-fit (BF) poses) when applying a given docking program over thousands/millions of molecules during virtual screening. To reduce this difficulty, two new procedures called Clusterizer and DockAccessor have been developed and implemented for use with some common and "free-for-academics" programs such as AutoDock4, AutoDock4(Zn), AutoDock Vina, DOCK, MpSDockZn, PLANTS, and Surflex-Dock to automatically extrapolate BD, BC, and BF poses as well as to perform consistent cluster and DA analyses. Clusterizer and DockAccessor (code available over the Internet) represent two novel tools to collect computationally determined poses and detect the most predictive docking approach. Herein an application to human lysine deacetylase (hKDAC) inhibitors is illustrated.

  • 4.
    Ballante, Flavio
    et al.
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Musmuca, Ira
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Marshall, Garland R
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
    Ragno, Rino
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Comprehensive model of wild-type and mutant HIV-1 reverse transciptases.2012In: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 26, no 8, p. 907-19Article in journal (Refereed)
    Abstract [en]

    An enhanced version of COMBINE that uses both ligand-based and structure-based alignment of ligands has been used to build a comprehensive 3-D QSAR model of wild-type HIV-1 reverse transcriptase and drug-resistant mutants. The COMBINEr model focused on 7 different RT enzymes complexed with just two HIV-RT inhibitors, niverapine (NVP) and efavirenz (EFV); therefore, 14 inhibitor/enzyme complexes comprised the training set. An external test set of chiral 2-(alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones (DABOs) was used to test predictability. The COMBINEr model MC4, although developed using only two inhibitors, predicted the experimental activities of the test set with an acceptable average absolute error of prediction (0.89 pK (i)). Most notably, the model was able to correctly predict the right eudismic ratio for two R/S pairs of DABO derivatives. The enhanced COMBINEr approach was developed using only software freely available to academics.

  • 5.
    Ballante, Flavio
    et al.
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P. le A. Moro 5, 00185, Rome, Italy.
    Ragno, Rino
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P. le A. Moro 5, 00185, Rome, Italy.
    3-D QSAutogrid/R: an alternative procedure to build 3-D QSAR models. Methodologies and applications.2012In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 52, no 6, p. 1674-85Article in journal (Refereed)
    Abstract [en]

    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.

  • 6.
    Ballante, Flavio
    et al.
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
    Reddy, D Rajasekhar
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
    Zhou, Nancy J
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
    Marshall, Garland R
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
    Structural insights of SmKDAC8 inhibitors: Targeting Schistosoma epigenetics through a combined structure-based 3D QSAR, in vitro and synthesis strategy.2017In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 25, no 7, p. 2105-2132, article id S0968-0896(16)31413-4Article in journal (Refereed)
    Abstract [en]

    A predictive structure-based 3D QSAR (COMBINEr 2.0) model of the Schistosoma mansoni lysine deacetylase 8 enzyme (SmKDAC8) was developed, validated and used to perform virtual screening (VS) of the NCI Diversity Set V database (1593 compounds). Three external datasets (with congeneric structures to those experimentally resolved in complexes by X-ray and previously reported as SmKDAC8 inhibitors) were employed to compose and validate the most predictive model. Two series characterized by 104 benzodiazepine derivatives (BZDs) and 60 simplified largazole analogs (SLAs), recently reported by our group as human KDAC inhibitors, were tested for their inhibition potency against SmKDAC8 to probe the predictive capability of the quantitative models against compounds with diverse structures. The SmKDAC8 biochemical results confirmed: (1) the benzodiazepine moiety as a valuable scaffold to further investigate when pursuing SmKDAC8 inhibition; (2) the predictive capability of the COMBINEr 2.0 model towards non-congeneric series of compounds, highlighting the most influencing ligand-protein interactions and refining the structure-activity relationships. From the VS investigations, the first 40 top-ranked compounds were obtained and biologically tested for their inhibition potency against SmKDAC8 and hKDACs 1, 3, 6 and 8. Among them, a non-hydroxamic acid benzothiadiazine dioxide derivative (code NSC163639), showed interesting activity and selectivity against SmKDAC8. To further elucidate the structure-activity relationships of NSC163639, two analogs (herein reported as compounds 3 and 4) were synthesized and biologically evaluated. Results suggest the benzothiadiazine dioxide moiety as a promising scaffold to be used in a next step to derive selective SmKDAC8 inhibitors.

  • 7.
    Caroli, Antonia
    et al.
    Department of Physics, Sapienza Universita ̀ di Roma, P.le Aldo Moro 5, 00185, Roma, Italy.
    Ballante, Flavio
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Roma, Italy.
    Wickersham, Richard B
    Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 63110, United States; Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Roma, Italy .
    Corelli, Federico
    Dipartimento Farmaco Chimico Tecnologico, Universita ̀ degli Studi di Siena, via A. Moro, I-53100 Siena, Italy.
    Ragno, Rino
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Roma, Italy.
    Hsp90 inhibitors, part 2: combining ligand-based and structure-based approaches for virtual screening application.2014In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 54, no 3, p. 970-7Article in journal (Refereed)
    Abstract [en]

    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.

  • 8.
    Friggeri, Laura
    et al.
    Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Ballante, Flavio
    Rome Center for Molecular Design Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Ragno, Rino
    Rome Center for Molecular Design Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Musmuca, Ira
    Rome Center for Molecular Design Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    De Vita, Daniela
    Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Manetti, Fabrizio
    Dipartimento di Biotecnologie, Chimica e Farmacia, Universita ̀ degli Studi di Siena, Via Aldo Moro 2, I-53100 Siena, Italy.
    Biava, Mariangela
    Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Scipione, Luigi
    Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Di Santo, Roberto
    Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Costi, Roberta
    Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Feroci, Marta
    Dipartimento di Scienze di Base e Applicate per l ’ Ingegneria, Sapienza Universita ̀ di Roma, Via Castro Laurenziano 7, I-00161 Rome, Italy.
    Tortorella, Silvano
    Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Pharmacophore assessment through 3-D QSAR: evaluation of the predictive ability on new derivatives by the application on a series of antitubercular agents.2013In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 53, no 6, p. 1463-74Article in journal (Refereed)
    Abstract [en]

    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.

  • 9.
    Kennedy, Amanda
    et al.
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
    Ballante, Flavio
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Johansson, Johan
    Cardiovascular Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
    Milligan, Graeme
    Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow.
    Sundström, Linda
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
    Nordqvist, Anneli
    Cardiovascular Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
    Carlsson, Jens
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Structural Characterization of Agonist Binding to Protease-Activated Receptor 2 through Mutagenesis and Computational Modeling2018In: ACS Pharmacology & Translational Science, ISSN 2575-9108, Vol. 1, no 2, p. 119-133Article in journal (Refereed)
    Abstract [en]

    Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor that is activated by proteolytic cleavage of its N-terminus. The unmasked N-terminal peptide then binds to the transmembrane bundle, leading to activation of intracellular signaling pathways associated with inflammation and cancer. Recently determined crystal structures have revealed binding sites of PAR2 antagonists, but the binding mode of the peptide agonist remains unknown. In order to generate a model of PAR2 in complex with peptide SLIGKV, corresponding to the trypsin-exposed tethered ligand, the orthosteric binding site was probed by iterative combinations of receptor mutagenesis, agonist ligand modifications and data-driven structural modeling. Flexible-receptor docking identified a conserved binding mode for agonists related to the endogenous ligand that was consistent with the experimental data and allowed synthesis of a novel peptide (1-benzyl-1H[1,2,3]triazole-4-yl-LIGKV) with higher functional potency than SLIGKV. The final model may be used to understand the structural basis of PAR2 activation and in virtual screens to identify novel PAR2 agonist and competitive antagonists. The combined experimental and computational approach to characterize agonist binding to PAR2 can be extended to study the many other G protein-coupled receptors that recognize peptides or proteins.

  • 10.
    Marshall, Garland R
    et al.
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States..
    Ballante, Flavio
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States..
    Limiting Assumptions in the Design of Peptidomimetics2017In: Drug development research (Print), ISSN 0272-4391, E-ISSN 1098-2299, Vol. 78, no 6, p. 245-267Article, review/survey (Refereed)
    Abstract [en]

    Limiting the flexibility of organic compounds to enhance their affinity and selectivity for targeting a macromolecule involved in molecular recognition has become a well-developed paradigm in medicinal chemistry. While the role of reverse-turn motifs as peptidomimetics has received the most attention, β-sheets and helices are also important motifs for protein/protein interactions. The more complicated problem of mimicking the interacting surface of noncontiguous epitopes will not be considered in this review. This limited overview focuses on efforts to use amino acid synthons as secondary-structure mimetics as well as providing examples of peptidomimetic design focused on nonpeptide synthetic chemistry in contrast. In particular, the rationale of optimal design criteria for mimicry and the many naïve violations of those criteria made in its pursuit are emphasized.

  • 11.
    Perspicace, Enrico
    et al.
    Laboratoire d ’ Ingénierie Moléculaire et Biochimie Pharmacologique, UMR CNRS 7565 SRSMC, Institut Jean Barriol, FR CNRS 2843, Université de Lorraine, 1 Boulevard Arago, 57070 Metz, France.
    Jouan-Hureaux, Valérie
    EA 4421 SiGReTO, Université de Lorraine, Faculté de pharmacie, 5-7 Rue Albert Lebrun, BP80403, 54001 Nancy cedex, France.
    Ragno, Rino
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “ La Sapienza ” , P. le A. Moro 5, 00185 Roma, Italy.
    Ballante, Flavio
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “ La Sapienza ” , P. le A. Moro 5, 00185 Roma, Italy.
    Sartini, Stefania
    Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
    La Motta, Concettina
    Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
    Da Settimo, Federico
    Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
    Chen, Binbin
    Laboratoire d ’ Ingénierie Moléculaire et Biochimie Pharmacologique, UMR CNRS 7565 SRSMC, Institut Jean Barriol, FR CNRS 2843, Université de Lorraine, 1 Boulevard Arago, 57070 Metz, France.
    Kirsch, Gilbert
    Laboratoire d ’ Ingénierie Moléculaire et Biochimie Pharmacologique, UMR CNRS 7565 SRSMC, Institut Jean Barriol, FR CNRS 2843, Université de Lorraine, 1 Boulevard Arago, 57070 Metz, France.
    Schneider, Serge
    Laboratoire National de Santé, Division de Toxicologie, Université de Luxembourg, 162a Avenue de la Faïencerie, L-1511 Luxembourg, Luxembourg.
    Faivre, Béatrice
    EA 4421 SiGReTO, Université de Lorraine, Faculté de pharmacie, 5-7 Rue Albert Lebrun, BP80403, 54001 Nancy cedex, France.
    Hesse, Stéphanie
    Laboratoire d ’ Ingénierie Moléculaire et Biochimie Pharmacologique, UMR CNRS 7565 SRSMC, Institut Jean Barriol, FR CNRS 2843, Université de Lorraine, 1 Boulevard Arago, 57070 Metz, France.
    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).2013In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 63, p. 765-81, article id S0223-5234(13)00170-0Article in journal (Refereed)
    Abstract [en]

    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.

  • 12.
    Ragno, Rino
    et al.
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy; Magma Dynamics srl, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Ballante, Flavio
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy; Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis School of Medicine, 700 South Euclid Avenue, St. Louis, MO 63110, USA.
    Pirolli, Adele
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Wickersham, Richard B
    Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis School of Medicine, 700 South Euclid Avenue, St. Louis, MO 63110, USA.
    Patsilinakos, Alexandros
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy; Magma Dynamics srl, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy .
    Hesse, Stéphanie
    SRSMC UMR CNRS7565 (former LIMBP), 1 Boulevard Arago, 57070 Metz, France.
    Perspicace, Enrico
    SRSMC UMR CNRS7565 (former LIMBP), 1 Boulevard Arago, 57070 Metz, France; Genfit, Parc Eurasante ́ , 885 Avenue Euge ` ne Avine ́ e, 59120 Loss, France.
    Kirsch, Gilbert
    SRSMC UMR CNRS7565 (former LIMBP), 1 Boulevard Arago, 57070 Metz, France.
    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.2015In: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 29, no 8, p. 757-76Article in journal (Refereed)
    Abstract [en]

    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.

  • 13.
    Ragno, Rino
    et al.
    Sapienza University of Rome.
    Marshall, Garland R.
    Washington University School of Medicine in St. Louis.
    Ballante, Flavio
    Washington University School of Medicine in St. Louis .
    Structure-based modeling and target-selectivity prediction2014Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    The present invention provides, inter alia, methods, models, and systems for selecting an effector having specificity for a target molecule. The methods and systems of the present invention involve several steps, including compiling a database containing structural data for a library of molecules and a population of ligands and activity data, establishing structure-based equivalence of sequence elements in the library of molecules, determining likely spatial orientations of population ligands in library molecules, calculating interaction energies for each ligand-molecule pair, generating statistical models that are predictive of sequence elements likely to contribute to a differential effect of ligands on molecules, selecting an effector that is likely to have a desired specificity for the target molecule, experimentally determining activity data for effector-library molecule pairs, and at least once repeating the steps listed above wherein the effector is a member of the population of ligands.

  • 14.
    Reddy, D Rajasekhar
    et al.
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
    Ballante, Flavio
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
    Zhou, Nancy J
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
    Marshall, Garland R
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
    Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors.2017In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 127, p. 531-553, article id S0223-5234(16)31038-8Article in journal (Refereed)
    Abstract [en]

    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.

  • 15.
    Reddy, Damodara N
    et al.
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
    Ballante, Flavio
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
    Chuang, Timothy
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
    Pirolli, Adele
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Roma, Italy.
    Marrocco, Biagina
    Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Roma, Italy.
    Marshall, Garland R
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
    Design and Synthesis of Simplified Largazole Analogues as Isoform-Selective Human Lysine Deacetylase Inhibitors.2016In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 4, p. 1613-33Article in journal (Refereed)
    Abstract [en]

    Selective inhibition of KDAC isoforms 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 analogue (SLA) scaffolds with diverse zinc-binding 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 zinc-binding group in the KDAC active site, providing a further basis for developing new KDACIs of higher isoform selectivity and potency.

  • 16.
    Rotili, Dante
    et al.
    Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy.
    Samuele, Alberta
    Istituto di Genetica Molecolare IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy.
    Tarantino, Domenico
    Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy.
    Ragno, Rino
    Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy.
    Musmuca, Ira
    Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy.
    Ballante, Flavio
    Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy.
    Botta, Giorgia
    Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy.
    Morera, Ludovica
    Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy.
    Pierini, Marco
    Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy.
    Cirilli, Roberto
    Dipartimento del Farmaco, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
    Nawrozkij, Maxim B
    Volgograd State Technical University, prospekt Lenina, 28, 400131 Volgograd, Russia.
    Gonzalez, Emmanuel
    Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain.
    Clotet, Bonaventura
    Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain.
    Artico, Marino
    Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy.
    Esté, José A
    Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain.
    Maga, Giovanni
    Istituto di Genetica Molecolare IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy.
    Mai, Antonello
    Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy.
    2-(Alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones as inhibitors of wild-type and mutant HIV-1: enantioselectivity studies.2012In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 7, p. 3558-62Article in journal (Refereed)
    Abstract [en]

    The single enantiomers of two pyrimidine-based HIV-1 non-nucleoside reverse transcriptase inhibitors, 1 (MC1501) and 2 (MC2082), were tested in both cellular and enzyme assays. In general, the R forms were more potent than their S counterparts and racemates and (R)-2 was more efficient than (R)-1 and the reference compounds, with some exceptions. Interestingly, (R)-2 displayed a faster binding to K103N RT with respect to WT RT, while (R)-1 showed the opposite behavior.

  • 17.
    Rotili, Dante
    et al.
    Dipartimento di Chimica e Tecnologie del Farmaco, Universita ̀ degli Studi di Roma “ La Sapienza ” , P.le A. Moro 5, 00185 Roma, Italy.
    Tarantino, Domenico
    Dipartimento di Chimica e Tecnologie del Farmaco, Universita ̀ degli Studi di Roma “ La Sapienza ” , P.le A. Moro 5, 00185 Roma, Italy.
    Nawrozkij, Maxim B
    Volgograd State Technical University, pr. Lenina, 28, 400131 Volgograd, Russia.
    Babushkin, Alexandre S
    Volgograd State Technical University, pr. Lenina, 28, 400131 Volgograd, Russia.
    Botta, Giorgia
    Dipartimento di Chimica e Tecnologie del Farmaco, Universita ̀ degli Studi di Roma “ La Sapienza ” , P.le A. Moro 5, 00185 Roma, Italy.
    Marrocco, Biagina
    Dipartimento di Chimica e Tecnologie del Farmaco, Universita ̀ degli Studi di Roma “ La Sapienza ” , P.le A. Moro 5, 00185 Roma, Italy.
    Cirilli, Roberto
    Dipartimento del Farmaco, Istituto Superiore di Sanita ̀ ,, Viale Regina Elena 299, 00161 Rome, Italy.
    Menta, Sergio
    Dipartimento di Chimica e Tecnologie del Farmaco, Universita ̀ degli Studi di Roma “ La Sapienza ” , P.le A. Moro 5, 00185 Roma, Italy.
    Badia, Roger
    IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Auto ̀ noma de Barcelona, 08916 Badalona, Spain.
    Crespan, Emmanuele
    Istituto di Genetica Molecolare IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy.
    Ballante, Flavio
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Universita ̀ degli Studi di Roma “ La Sapienza ” , P.le A. Moro 5, 00185 Roma, Italy; Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 00185, United States.
    Ragno, Rino
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Universita ̀ degli Studi di Roma “ La Sapienza ” , P.le A. Moro 5, 00185 Roma, Italy.
    Esté, José A
    IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Auto ̀ noma de Barcelona, 08916 Badalona, Spain.
    Maga, Giovanni
    Istituto di Genetica Molecolare IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy.
    Mai, Antonello
    Dipartimento di Chimica e Tecnologie del Farmaco, Universita ̀ degli Studi di Roma “ La Sapienza ” , P.le A. Moro 5, 00185 Roma, Italy; Istituto Pasteur  Fondazione Cenci Bolognetti, Universita ̀ degli Studi di Roma “ La Sapienza ” , P.le A. Moro 5, 00185 Roma, Italy.
    Exploring the role of 2-chloro-6-fluoro substitution in 2-alkylthio-6-benzyl-5-alkylpyrimidin-4(3H)-ones: effects in HIV-1-infected cells and in HIV-1 reverse transcriptase enzymes.2014In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 12, p. 5212-25Article in journal (Refereed)
    Abstract [en]

    A comparison of the effects of the 6-(2-chloro-6-fluorobenzyl)-2-(alkylthio)pyrimidin-4(3H)-ones (2-Cl-6-F-S-DABOs) 7-12 and the related 6-(2,6-difluorobenzyl) counterparts 13-15 in HIV-1 infected cells and in the HIV-1 reverse transcriptase (RT) assays is here described. The new 2-Cl-6-F-S-DABOs showed up to picomolar activity against wt HIV-1. Against clinically relevant HIV-1 mutants and in enzyme assays, the simultaneous C5(methyl)/C6(methyl/ethyl) substitution in the 2-Cl-6-F- and 2,6-F2-benzyl series furnished compounds with the highest, wide-spectrum inhibitory activity against HIV-1. Three representative 2-Cl-6-F-S-DABOs carrying two (9c, 10c) or one (10a) stereogenic centers were resolved into their individual stereoisomers and showed a significant diastereo- and enantioselectivity in HIV-1 inhibition, the highest antiviral activity well correlating with the R absolute configuration to the stereogenic center of the C6-benzylic position in both cellular and enzymatic tests. Application of previously reported COMBINEr protocol on 9c and 10c confirmed the influence of the stereogenic centers on their binding modes in the HIV-1 RT.

  • 18.
    Silvestri, Laura
    et al.
    Rome Center for Molecular Design Dipartimento di Chimica e Tecnologie del Farmaco, Facolta ̀ di Farmacia e Medicina.
    Ballante, Flavio
    Rome Center for Molecular Design Dipartimento di Chimica e Tecnologie del Farmaco, Facolta ̀ di Farmacia e Medicina.
    Mai, Antonello
    Istituto Pasteur - Fondazione Cenci Bolognetti Dipartimento di Chimica e Tecnologie del Farmaco, Facolta ̀ di Farmacia e Medicina.
    Marshall, Garland R
    Rome Center for Molecular Design Dipartimento di Chimica e Tecnologie del Farmaco, Facolta ̀ di Farmacia e Medicina; Visiting Professor from the Department of Biochemistry and Molecular Biophysics, Wash ington University School of Medicine, St. Louis, Missouri 63110, United States.
    Ragno, Rino
    Rome Center for Molecular Design Dipartimento di Chimica e Tecnologie del Farmaco, Facolta ̀ di Farmacia e Medicina.
    Histone deacetylase inhibitors: structure-based modeling and isoform-selectivity prediction.2012In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 52, no 8, p. 2215-35Article in journal (Refereed)
    Abstract [en]

    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.

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