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  1. Article: Rethinking to riluzole mechanism of action: the molecular link among protein kinase CK1δ activity, TDP-43 phosphorylation, and amyotrophic lateral sclerosis pharmacological treatment.

    Bissaro, Maicol / Moro, Stefano

    Neural regeneration research

    2019  Volume 14, Issue 12, Page(s) 2083–2085

    Language English
    Publishing date 2019-08-09
    Publishing country India
    Document type Journal Article
    ZDB-ID 2388460-5
    ISSN 1876-7958 ; 1673-5374
    ISSN (online) 1876-7958
    ISSN 1673-5374
    DOI 10.4103/1673-5374.262578
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Computational Strategies to Identify New Drug Candidates against Neuroinflammation.

    Pavan, Matteo / Bassani, Davide / Bolcato, Giovanni / Bissaro, Maicol / Sturlese, Mattia / Moro, Stefano

    Current medicinal chemistry

    2022  Volume 29, Issue 27, Page(s) 4756–4775

    Abstract: Increasing application of computational approaches in these last decades has deeply modified the process of discovery and commercialization of new therapeutic entities. This is especially true in the field of neuroinflammation, in which both the peculiar ...

    Abstract Increasing application of computational approaches in these last decades has deeply modified the process of discovery and commercialization of new therapeutic entities. This is especially true in the field of neuroinflammation, in which both the peculiar anatomical localization and the presence of the blood-brain barrier make it mandatory to finely tune the candidates' physicochemical properties from the early stages of the discovery pipeline. The aim of this review is, therefore, to provide a general overview of neuroinflammation to the readers, together with the most common computational strategies that can be exploited to discover and design small molecules controlling neuroinflammation, especially those based on the knowledge of the three-dimensional structure of the biological targets of therapeutic interest. The techniques used to describe the molecular recognition mechanisms, such as molecular docking and molecular dynamics, will therefore be discussed, highlighting their advantages and limitations. Finally, we report several case studies in which computational methods have been applied to drug discovery for neuroinflammation, focusing on the research conducted in the last decade.
    MeSH term(s) Blood-Brain Barrier ; Drug Design ; Drug Discovery/methods ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Neuroinflammatory Diseases
    Language English
    Publishing date 2022-02-08
    Publishing country United Arab Emirates
    Document type Journal Article ; Review
    ZDB-ID 1319315-6
    ISSN 1875-533X ; 0929-8673
    ISSN (online) 1875-533X
    ISSN 0929-8673
    DOI 10.2174/0929867329666220208095122
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4432: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article: Exploring the RNA-Recognition Mechanism Using Supervised Molecular Dynamics (SuMD) Simulations: Toward a Rational Design for Ribonucleic-Targeting Molecules?

    Bissaro, Maicol / Sturlese, Mattia / Moro, Stefano

    Frontiers in chemistry

    2020  Volume 8, Page(s) 107

    Abstract: Although proteins have represented the molecular target of choice in the development of new drug candidates, the pharmaceutical importance of ribonucleic acids has gradually been growing. The increasing availability of structural information has brought ... ...

    Abstract Although proteins have represented the molecular target of choice in the development of new drug candidates, the pharmaceutical importance of ribonucleic acids has gradually been growing. The increasing availability of structural information has brought to light the existence of peculiar three-dimensional RNA arrangements, which can, contrary to initial expectations, be recognized and selectively modulated through small chemical entities or peptides. The application of classical computational methodologies, such as molecular docking, for the rational development of RNA-binding candidates is, however, complicated by the peculiarities characterizing these macromolecules, such as the marked conformational flexibility, the singular charges distribution, and the relevant role of solvent molecules. In this work, we have thus validated and extended the applicability domain of SuMD, an all-atoms molecular dynamics protocol that allows to accelerate the sampling of molecular recognition events on a nanosecond timescale, to ribonucleotide targets of pharmaceutical interest. In particular, we have proven the methodological ability by reproducing the binding mode of viral or prokaryotic ribonucleic complexes, as well as that of artificially engineered aptamers, with an impressive degree of accuracy.
    Keywords covid19
    Language English
    Publishing date 2020-02-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2711776-5
    ISSN 2296-2646
    ISSN 2296-2646
    DOI 10.3389/fchem.2020.00107
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  4. Article ; Online: Comparing Fragment Binding Poses Prediction Using HSP90 as a Key Study: When Bound Water Makes the Difference.

    Bolcato, Giovanni / Bissaro, Maicol / Sturlese, Mattia / Moro, Stefano

    Molecules (Basel, Switzerland)

    2020  Volume 25, Issue 20

    Abstract: Fragment-Based Drug Discovery (FBDD) approaches have gained popularity not only in industry but also in academic research institutes. However, the computational prediction of the binding mode adopted by fragment-like molecules within a protein binding ... ...

    Abstract Fragment-Based Drug Discovery (FBDD) approaches have gained popularity not only in industry but also in academic research institutes. However, the computational prediction of the binding mode adopted by fragment-like molecules within a protein binding site is still a very challenging task. One of the most crucial aspects of fragment binding is related to the large amounts of bound waters in the targeted binding pocket. The binding affinity of fragments may not be sufficient to displace the bound water molecules. In the present work, we confirmed the importance of the bound water molecules in the correct prediction of the fragment binding mode. Moreover, we investigate whether the use of methods based on explicit solvent molecular dynamics simulations can improve the accuracy of fragment posing. The protein chosen for this study is HSP-90.
    MeSH term(s) Animals ; Binding Sites ; Drug Design ; HSP90 Heat-Shock Proteins/analysis ; Humans ; Molecular Dynamics Simulation ; Water
    Chemical Substances HSP90 Heat-Shock Proteins ; Water (059QF0KO0R)
    Language English
    Publishing date 2020-10-12
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules25204651
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.MO 81: Show issues

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  5. Article ; Online: The rise of molecular simulations in fragment-based drug design (FBDD): an overview.

    Bissaro, Maicol / Sturlese, Mattia / Moro, Stefano

    Drug discovery today

    2020  Volume 25, Issue 9, Page(s) 1693–1701

    Abstract: Fragment-based drug discovery (FBDD) is an innovative approach, progressively more applied in the academic and industrial context, to enhance hit identification for previously considered undruggable biological targets. In particular, FBDD discovers low- ... ...

    Abstract Fragment-based drug discovery (FBDD) is an innovative approach, progressively more applied in the academic and industrial context, to enhance hit identification for previously considered undruggable biological targets. In particular, FBDD discovers low-molecular-weight (LMW) ligands (<300Da) able to bind to therapeutically relevant macromolecules in an affinity range from the micromolar (μM) to millimolar (mM). X-ray crystallography (XRC) and nuclear magnetic resonance (NMR) spectroscopy are commonly the methods of choice to obtain 3D information about the bound ligand-protein complex, but this can occasionally be problematic, mainly for early, low-affinity fragments. The recent development of computational fragment-based approaches provides a further strategy for improving the identification of fragment hits. In this review, we summarize the state of the art of molecular dynamics simulations approaches used in FBDD, and discuss limitations and future perspectives for these approaches.
    MeSH term(s) Binding Sites ; Drug Design ; Drug Discovery ; Molecular Dynamics Simulation
    Keywords covid19
    Language English
    Publishing date 2020-06-25
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1324988-5
    ISSN 1878-5832 ; 1359-6446
    ISSN (online) 1878-5832
    ISSN 1359-6446
    DOI 10.1016/j.drudis.2020.06.023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4725: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  6. Article: Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular Dynamics.

    Hassankalhori, Mahdi / Bolcato, Giovanni / Bissaro, Maicol / Sturlese, Mattia / Moro, Stefano

    Frontiers in molecular biosciences

    2021  Volume 8, Page(s) 707661

    Abstract: Macrocycles are attractive structures for drug development due to their favorable structural features, potential in binding to targets with flat featureless surfaces, and their ability to disrupt protein-protein interactions. Moreover, large novel highly ...

    Abstract Macrocycles are attractive structures for drug development due to their favorable structural features, potential in binding to targets with flat featureless surfaces, and their ability to disrupt protein-protein interactions. Moreover, large novel highly diverse libraries of low-molecular-weight macrocycles with therapeutically favorable characteristics have been recently established. Considering the mentioned facts, having a validated, fast, and accurate computational protocol for studying the molecular recognition and binding mode of this interesting new class of macrocyclic peptides deemed to be helpful as well as insightful in the quest of accelerating drug discovery. To that end, the ability of the in-house supervised molecular dynamics protocol called SuMD in the reproduction of the X-ray crystallography final binding state of a macrocyclic non-canonical tetrapeptide-from a novel library of 8,988 sub-kilodalton macrocyclic peptides-in the thrombin active site was successfully validated. A comparable binding mode with the minimum root-mean-square deviation (RMSD) of 1.4 Å at simulation time point 71.6 ns was achieved. This method validation study extended the application domain of the SuMD sampling method for computationally cheap, fast but accurate, and insightful macrocycle-protein molecular recognition studies.
    Language English
    Publishing date 2021-08-31
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2814330-9
    ISSN 2296-889X
    ISSN 2296-889X
    DOI 10.3389/fmolb.2021.707661
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Comparing Fragment Binding PosesPrediction Using HSP90 as a Key Study

    Giovanni Bolcato / Maicol Bissaro / Mattia Sturlese / Stefano Moro

    Molecules, Vol 25, Iss 4651, p

    When Bound Water Makes the Difference

    2020  Volume 4651

    Abstract: Fragment-Based Drug Discovery (FBDD) approaches have gained popularity not only in industry but also in academic research institutes.However, the computational prediction of the binding mode adopted by fragment-like molecules within a protein binding ... ...

    Abstract Fragment-Based Drug Discovery (FBDD) approaches have gained popularity not only in industry but also in academic research institutes.However, the computational prediction of the binding mode adopted by fragment-like molecules within a protein binding site is still a very challenging task. One of the most crucial aspects of fragment binding is related to the large amounts of bound waters in the targeted binding pocket. The binding affinity of fragmentsmay not be sufficientto displace the bound water molecules. In the present work, we confirmed the importance of the bound water molecules in the correct prediction of the fragment binding mode.Moreover, we investigate whether the use of methods based on explicit solvent molecular dynamics simulations can improve the accuracy of fragment posing. The protein chosen for this study is HSP-90.
    Keywords fragment-based drug discovery ; molecular docking ; molecular dynamics ; supervised molecular dynamics ; water ; HSP-90 ; Organic chemistry ; QD241-441
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Exploring the RNA-Recognition Mechanism Using Supervised Molecular Dynamics (SuMD) Simulations

    Maicol Bissaro / Mattia Sturlese / Stefano Moro

    Frontiers in Chemistry, Vol

    Toward a Rational Design for Ribonucleic-Targeting Molecules?

    2020  Volume 8

    Abstract: Although proteins have represented the molecular target of choice in the development of new drug candidates, the pharmaceutical importance of ribonucleic acids has gradually been growing. The increasing availability of structural information has brought ... ...

    Abstract Although proteins have represented the molecular target of choice in the development of new drug candidates, the pharmaceutical importance of ribonucleic acids has gradually been growing. The increasing availability of structural information has brought to light the existence of peculiar three-dimensional RNA arrangements, which can, contrary to initial expectations, be recognized and selectively modulated through small chemical entities or peptides. The application of classical computational methodologies, such as molecular docking, for the rational development of RNA-binding candidates is, however, complicated by the peculiarities characterizing these macromolecules, such as the marked conformational flexibility, the singular charges distribution, and the relevant role of solvent molecules. In this work, we have thus validated and extended the applicability domain of SuMD, an all-atoms molecular dynamics protocol that allows to accelerate the sampling of molecular recognition events on a nanosecond timescale, to ribonucleotide targets of pharmaceutical interest. In particular, we have proven the methodological ability by reproducing the binding mode of viral or prokaryotic ribonucleic complexes, as well as that of artificially engineered aptamers, with an impressive degree of accuracy.
    Keywords nucleic acids ; RNA ; SMIRNA ; molecular recognition ; molecular dynamics (MD) ; supervised molecular dynamics (SuMD) ; Chemistry ; QD1-999
    Subject code 541
    Language English
    Publishing date 2020-02-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular Dynamics

    Mahdi Hassankalhori / Giovanni Bolcato / Maicol Bissaro / Mattia Sturlese / Stefano Moro

    Frontiers in Molecular Biosciences, Vol

    2021  Volume 8

    Abstract: Macrocycles are attractive structures for drug development due to their favorable structural features, potential in binding to targets with flat featureless surfaces, and their ability to disrupt protein–protein interactions. Moreover, large novel highly ...

    Abstract Macrocycles are attractive structures for drug development due to their favorable structural features, potential in binding to targets with flat featureless surfaces, and their ability to disrupt protein–protein interactions. Moreover, large novel highly diverse libraries of low-molecular-weight macrocycles with therapeutically favorable characteristics have been recently established. Considering the mentioned facts, having a validated, fast, and accurate computational protocol for studying the molecular recognition and binding mode of this interesting new class of macrocyclic peptides deemed to be helpful as well as insightful in the quest of accelerating drug discovery. To that end, the ability of the in-house supervised molecular dynamics protocol called SuMD in the reproduction of the X-ray crystallography final binding state of a macrocyclic non-canonical tetrapeptide—from a novel library of 8,988 sub-kilodalton macrocyclic peptides—in the thrombin active site was successfully validated. A comparable binding mode with the minimum root-mean-square deviation (RMSD) of 1.4 Å at simulation time point 71.6 ns was achieved. This method validation study extended the application domain of the SuMD sampling method for computationally cheap, fast but accurate, and insightful macrocycle–protein molecular recognition studies.
    Keywords molecular recognition ; macrocyclic ; supervised molecular dynamics ; thrombin ; tetrapeptide ; Biology (General) ; QH301-705.5
    Subject code 541
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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  10. Article ; Online: New Insights into Key Determinants for Adenosine 1 Receptor Antagonists Selectivity Using Supervised Molecular Dynamics Simulations.

    Bolcato, Giovanni / Bissaro, Maicol / Deganutti, Giuseppe / Sturlese, Mattia / Moro, Stefano

    Biomolecules

    2020  Volume 10, Issue 5

    Abstract: Adenosine receptors (ARs), like many otherGprotein-coupledreceptors (GPCRs), are targets of primary interest indrug design. However, one of the main limits for the development of drugs for this class of GPCRs is the complex selectivity profile usually ... ...

    Abstract Adenosine receptors (ARs), like many otherGprotein-coupledreceptors (GPCRs), are targets of primary interest indrug design. However, one of the main limits for the development of drugs for this class of GPCRs is the complex selectivity profile usually displayed by ligands. Numerous efforts have been madefor clarifying the selectivity of ARs, leading to the development of many ligand-based models. The structure of the AR subtype A
    MeSH term(s) Adenosine A1 Receptor Antagonists/chemistry ; Adenosine A1 Receptor Antagonists/pharmacology ; Binding Sites ; Humans ; Molecular Docking Simulation/methods ; Molecular Dynamics Simulation ; Protein Binding ; Receptor, Adenosine A1/chemistry ; Receptor, Adenosine A1/metabolism ; Supervised Machine Learning
    Chemical Substances Adenosine A1 Receptor Antagonists ; Receptor, Adenosine A1
    Language English
    Publishing date 2020-05-07
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2701262-1
    ISSN 2218-273X ; 2218-273X
    ISSN (online) 2218-273X
    ISSN 2218-273X
    DOI 10.3390/biom10050732
    Database MEDical Literature Analysis and Retrieval System OnLINE

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