Giulio Rastelli

Università degli Studi di Modena e Reggio Emilia, Modène, Emilia-Romagna, Italy

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Publications (91)273.75 Total impact

  • Macromolecules 09/2015; DOI:10.1021/acs.macromol.5b01598 · 5.80 Impact Factor
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    Giulio Rastelli · Luca Pinzi
    Frontiers in Pharmacology 08/2015; 6:157. DOI:10.3389/fphar.2015.00157 · 3.80 Impact Factor
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    ABSTRACT: This study describe the discovery of novel dengue virus inhibitors targeting both a crucial viral protein-protein interaction and an essential host cell factor as a strategy to reduce the emergence of drug-resistance. Starting from known c-Src inhibitors, a virtual screening was performed to identify molecules able to interact with a recently discovered allosteric pocket on the dengue virus NS5 polymerase. The selection of cheap-to-produce scaffolds and the exploration of the biologically relevant chemical space around them suggested promising candidates for chemical synthesis. A series of purines emerged as the most interesting candidates able to inhibit virus replication at low micromolar concentrations with no significant toxicity to the host cell. Among the identified antivirals, compound 16i proved to be ten times more potent than ribavirin, showed a better selectivity index and represents the first-in-class DENV-NS5 allosteric inhibitor able to target both the virus NS5-NS3 interaction and the host kinases c-Src/Fyn.
    Journal of Medicinal Chemistry 06/2015; 58(12). DOI:10.1021/acs.jmedchem.5b00108 · 5.45 Impact Factor
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    ABSTRACT: Metabotropic glutamate receptor 5 (mGlu5) is a biological target implicated in major neurological and psychiatric disorders. In the present study, we have investigated structural determinants of the interaction of negative allosteric modulators (NAMs) with the seven-transmembrane (7TM) domain of mGlu5. A homology model of the 7TM receptor domain built on the crystal structure of the mGlu1 template was obtained, and the binding modes of known NAMs, namely MPEP and fenobam, were investigated by docking and molecular dynamics simulations. The results were validated by comparison with mutagenesis data available in the literature for these two ligands, and subsequently corroborated by the recently described mGlu5 crystal structure. Moreover, a new series of NAMs was synthesized and tested, providing compounds with nanomolar affinity. Several structural modifications were sequentially introduced with the aim of identifying structural features important for receptor binding. The synthesized NAMs were docked in the validated homology model and binding modes were used to interpret and discuss structure-activity relationships within this new series of compounds. Finally, the models of the interaction of NAMs with mGlu5 were extended to include important non-aryl alkyne mGlu5 NAMs taken from the literature. Overall, the results provide useful insights into the molecular interaction of negative allosteric modulators with mGlu5 and may facilitate the design of new modulators for this class of receptors. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Bioorganic & Medicinal Chemistry 05/2015; 23(13). DOI:10.1016/j.bmc.2015.05.008 · 2.79 Impact Factor
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    ABSTRACT: The design of a single drug molecule able to simultaneously and specifically interact with multiple biological targets is gaining major consideration in drug discovery. However, the rational design of drugs with a desired polypharmacology profile is still a challenging task, especially when these targets are distantly related or unrelated. In this work, we present a computational approach aiming at the identification of suitable target combinations for multitarget drug design within an ensemble of biologically relevant proteins. The target selection relies on the analysis of activity annotations present in molecular databases and on ligand-based virtual screening. A few target combinations were also inspected with structure-based methods to demonstrate that the identified dual activity compounds are able to bind target combinations characterized by remote binding site similarities. Our approach was applied to the heat shock protein 90 (Hsp90) interactome, which contains several targets of key importance in cancer. Promising target combinations were identified, providing a basis for the computational design of compounds with dual activity. The approach may be used on any ensemble of proteins of interest for which known inhibitors are available.
    Journal of Chemical Information and Modeling 02/2015; 55(3). DOI:10.1021/ci5006959 · 3.74 Impact Factor
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    Carmina Micelli · Giulio Rastelli
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    ABSTRACT: Histone deacetylases (HDACs) are epigenetic targets playing an important role in cancer, neurodegeneration, inflammation, and metabolic disorders. Although clinically effective HDAC inhibitors have been developed, the design of inhibitors with the desired isoform(s) selectivity still remains a challenge. Selective inhibitors could help clarify the function of each isoform, and provide therapeutic agents having potentially fewer side effects. Crystal structures of several HDACs have been reported, enabling structure-based drug design and providing important information to understand enzyme function. Here we provide a comprehensive review of the structural information available on HDACs, discussing both conserved and isoform-specific structural and mechanistic features. We focus on distinctive aspects that help rationalize inhibitor selectivity, and provide structure-based recommendations for achieving the desired selectivity. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Drug Discovery Today 02/2015; 20(6). DOI:10.1016/j.drudis.2015.01.007 · 6.69 Impact Factor
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    ABSTRACT: This study aimed to explore the capability of potentially probiotic bifidobacteria to hydrolyze chlorogenic acid into caffeic acid (CA), and to recognize the enzymes involved in this reaction. Bifidobacterium strains belonging to eight species occurring in the human gut were screened. The hydrolysis seemed peculiar of Bifidobacterium animalis, whereas the other species failed to release CA. Intracellular feruloyl esterase activity capable of hydrolyzing chlorogenic acid was detected only in B. animalis. In silico research among bifidobacteria esterases identified Balat_0669 as the cytosolic enzyme likely responsible of CA release in B. animalis. Comparative modeling of Balat_0669 and molecular docking studies support its role in chlorogenic acid hydrolysis. Expression, purification, and functional characterization of Balat_0669 in Escherichia coli were obtained as further validation. A possible role of B. animalis in the activation of hydroxycinnamic acids was demonstrated and new perspectives were opened in the development of new probiotics, specifically selected for the enhanced bioconversion of phytochemicals into bioactive compounds.
    MicrobiologyOpen 02/2015; 4(1):41-52. DOI:10.1002/mbo3.219 · 2.21 Impact Factor
  • Andrew Anighoro · Jürgen Bajorath · Giulio Rastelli
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    ABSTRACT: At present, the legendary magic bullet, i.e. a drug with high potency and selectivity towards a specific biological target, shares the spotlight with an emerging and alternative polypharmacology approach. Polypharmacology suggests that more effective drugs can be developed by specifically modulating multiple targets. It is generally thought that complex diseases such as cancer and central nervous system diseases may require complex therapeutic approaches. In this respect, a drug that "hits" multiple sensitive nodes belonging to a network of interacting targets offers the potential for higher efficacy, and may limit drawbacks generally arising from the use of a single-target drug or a combination of multiple drugs. In this article, we will compare advantages and disadvantages of multi-target versus combination therapies, discuss potential drug promiscuity arising from off-target effects, comment on drug repurposing, and introduce approaches to the computational design of multi-target drugs.
    Journal of Medicinal Chemistry 06/2014; 57(19). DOI:10.1021/jm5006463 · 5.45 Impact Factor
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    ABSTRACT: Allosteric targeting of protein kinases via displacement of the structural αC helix with type III allosteric inhibitors is currently gaining a foothold in drug discovery. Recently, the first crystal structure of CDK2 with an open allosteric pocket adjacent to the αC helix has been described, prospecting new opportunities to design more selective inhibitors, but the structure has not yet been exploited for the structure-based design of type III allosteric inhibitors. In this work we report the results of a virtual screening campaign that resulted in the discovery of the first-in-class type III allosteric ligands of CDK2. Using a combination of docking and post-docking analyses made with our tool BEAR, 7 allosteric ligands (hit rate of 20%) with micromolar affinity for CDK2 were identified, some of them inhibiting the growth of breast cancer cell lines in the micromolar range. Competition experiments performed in the presence of the ATP-competitive inhibitor staurosporine confirmed that the 7 ligands are truly allosteric, in agreement with their design. Of these, compound 2 bound CDK2 with an EC 50 value of 3 μM and inhibited the proliferation of MDA-MB231 and ZR-75-1 breast cancer cells with IC 50 values of approximately 20 μM, while compound 4 had an EC 50 value of 71 μM and IC 50 values around 4 μM. Remarkably, the most potent compound 4 was able to selectively inhibit CDK2-mediated Retinoblastoma phosphorylation, confirming that its mechanism of action is fully compatible with a selective inhibition of CDK2 phosphorylation in cells. Finally, hit expansion through analog search of the most potent inhibitor 4 revealed an additional ligand 4g with similar in vitro potency on breast cancer cells.
    Cell cycle (Georgetown, Tex.) 06/2014; 13(14). DOI:10.4161/cc.29295 · 4.57 Impact Factor
  • Giulio Rastelli
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    ABSTRACT: Dimerization is an essential step of the Hsp90 cycle. This work describes the results of molecular dynamics and dimerization free energy analyses performed on the structure of the human Hsp90 closed dimer. Free energy decomposition on a domain- and residue-basis highlighted different dimerization hot spots within the dimer interface that could provide binding sites for the design of allosteric inhibitors.
    Medicinal Chemistry Communication 06/2014; 5(6):797. DOI:10.1039/c4md00094c · 2.50 Impact Factor
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    Giulio Rastelli · Maria Paola Costi
    Computational and Theoretical Chemistry 04/2014; 1058. DOI:10.1016/j.comptc.2014.03.012 · 1.55 Impact Factor
  • Andrew Anighoro · Giulio Rastelli
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    ABSTRACT: G-protein coupled receptors (GPCRs) are highly relevant drug targets. Four GPCRs with known crystal structure were analyzed with docking (AutoDock4) and post-docking (MM-PBSA) in order to evaluate the ability to recognize known antagonists from a larger database of molecular decoys and to predict correct binding modes. Moreover, implications on multitarget drug screening are put forward. The results suggest that these methods may be of interest to the growing field of GPCR structure based virtual screening.
    Journal of Chemical Information and Modeling 03/2013; 53(4). DOI:10.1021/ci4000745 · 3.74 Impact Factor
  • Giulio Rastelli
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    ABSTRACT: Molecular dynamics simulations and the generation of ad hoc chemical libraries are playing an increasingly important and recognized role in structure-based virtual screening. These approaches are important for treating target flexibility and improving the drug discovery pipeline. In this article I will comment on these two topics and put them into perspective.
    Pharmaceutical Research 03/2013; 30(5). DOI:10.1007/s11095-013-1012-9 · 3.42 Impact Factor
  • Andrew Anighoro · Giulio Rastelli
    Computational Molecular Bioscience 01/2013; 03(02):27-31. DOI:10.4236/cmb.2013.32004
  • Lorenzo Palmieri · Giulio Rastelli
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    ABSTRACT: Displacement of the αC helix in kinases by allosteric modulators is becoming a prominent approach in drug discovery, owing to its potential ability to provide inhibitor selectivity. According to recent evidence, this approach appears to be more generally applicable to a broader number of kinases of the human kinome than was previously expected. Owing to their crucial role in the modulation of cell pathways, protein kinases are important targets for a number of human diseases, including but not limited to cancer. The classic approach of targeting the ATP active site has recently come up against selectivity issues, which can be considerably reduced by following an allosteric modulation approach. Being closely related to protein kinase inactivation, allosteric targeting via displacement of the conserved structural αC helix enables a direct and specific modulation mechanism. A structure-based survey of the allosteric regulation of αC helix conformation in various kinase families is provided, highlighting key allosteric pockets and modulation mechanisms that appear to be more broadly conserved than was previously thought.
    Drug discovery today 11/2012; 18(7-8). DOI:10.1016/j.drudis.2012.11.009 · 6.69 Impact Factor
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    ABSTRACT: In the last decades, molecular docking has emerged as an increasingly useful tool in the modern drug discovery process, but it still needs to overcome many hurdles and limitations such as how to account for protein flexibility and poor scoring function performance. For this reason, it has been recognized that in many cases docking results need to be post-processed to achieve a significant agreement with experimental activities. In this study, we have evaluated the performance of MM-PBSA and MM-GBSA scoring functions, implemented in our post-docking procedure BEAR, in rescoring docking solutions. For the first time, the performance of this post-docking procedure has been evaluated on six different biological targets (namely estrogen receptor, thymidine kinase, factor Xa, adenosine deaminase, aldose reductase, and enoyl ACP reductase) by using i) both a single and a multiple protein conformation approach, and ii) two different software, namely AutoDock and LibDock. The assessment has been based on two of the most important criteria for the evaluation of docking methods, i.e., the ability of known ligands to enrich the top positions of a ranked database with respect to molecular decoys, and the consistency of the docking poses with crystallographic binding modes. We found that, in many cases, MM-PBSA and MM-GBSA are able to yield higher enrichment factors compared to those obtained with the docking scoring functions alone. However, for only a minority of the cases, the enrichment factors obtained by using multiple protein conformations were higher than those obtained by using only one protein conformation.
    European Journal of Medicinal Chemistry 10/2012; 58C:431-440. DOI:10.1016/j.ejmech.2012.10.024 · 3.45 Impact Factor
  • Marco Daniele Parenti · Giulio Rastelli
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    ABSTRACT: Nowadays, the improvement of R&D productivity is the primary commitment in pharmaceutical research, both in big pharma and smaller biotech companies. To reduce costs, to speed up the discovery process and to increase the chance of success, advanced methods of rational drug design are very helpful, as demonstrated by several successful applications. Among these, computational methods able to predict the binding affinity of small molecules to specific biological targets are of special interest because they can accelerate the discovery of new hit compounds. Here we provide an overview of the most widely used methods in the field of binding affinity prediction, as well as of our own work in developing BEAR, an innovative methodology specifically devised to overtake some limitations in existing approaches. The BEAR method was successfully validated against different biological targets, and proved its efficacy in retrieving active compounds from virtual screening campaigns. The results obtained so far indicate that BEAR may become a leading tool in the drug discovery pipeline. We primarily discuss advantages and drawbacks of each technique and show relevant examples and applications in drug discovery.
    Biotechnology advances 08/2011; 30(1):244-50. DOI:10.1016/j.biotechadv.2011.08.003 · 9.02 Impact Factor
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    ABSTRACT: Cytochrome P450 aromatase catalyzes the conversion of androgen substrates into estrogens. Aromatase inhibitors (AIs) have been used as first-line drugs in the treatment of estrogen-dependent breast cancer in postmenopausal women. However, the search for new, more potent, and selective AIs still remains necessary to avoid the risk of possible resistances and reduce toxicity and side effects of current available drugs. The publication of a high resolution X-ray structure of human aromatase has opened the way to structure-based virtual screening to identify new small-molecule inhibitors with structural motifs different from all known AIs. In this context, a high-throughput docking protocol was set up and led to the identification of nanomolar AIs with new core structures.
    Journal of Medicinal Chemistry 06/2011; 54(12):4006-17. DOI:10.1021/jm2000689 · 5.45 Impact Factor
  • Elena Muzzioli · Alberto Del Rio · Giulio Rastelli
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    ABSTRACT: An application of molecular dynamics and molecular mechanics Poisson-Boltzmann surface area techniques to the prediction of protein kinase inhibitor selectivity is presented. A highly active and selective ERK2 inhibitor was placed in equivalent orientations in five different protein kinases (SRC, LCK, GSK3, JNK3 and Aurora-A). Binding free energies were then computed with the molecular mechanics Poisson-Boltzmann surface area approach using 15 nanosecond fully solvated molecular dynamics trajectories of the corresponding protein-ligand complexes. The results show correlation with experimentally determined selectivities and provide useful insights into the underlying structural determinants for selectivity.
    Chemical Biology &amp Drug Design 05/2011; 78(2):252-9. DOI:10.1111/j.1747-0285.2011.01140.x · 2.49 Impact Factor
  • Journal of Biotechnology 11/2010; 150:94-95. DOI:10.1016/j.jbiotec.2010.08.244 · 2.87 Impact Factor

Publication Stats

2k Citations
273.75 Total Impact Points


  • 1995–2015
    • Università degli Studi di Modena e Reggio Emilia
      • • Department of Life Sciences
      • • Department of Biomedical, Metabolical and Neurosciences
      Modène, Emilia-Romagna, Italy
  • 2010
    • Università degli Studi di Sassari
      • Department of Chemistry and Pharmacy
      Sassari, Sardinia, Italy
  • 1997
    • Università Politecnica delle Marche
      • Chair of Biological Sciences
      Ancona, The Marches, Italy