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  1. Article ; Online: Identification of Potential Inhibitors of the SARS-CoV-2 NSP13 Helicase via Structure-Based Ligand Design, Molecular Docking and Nonequilibrium Alchemical Simulations.

    Di Paco, Giorgio / Macchiagodena, Marina / Procacci, Piero

    ChemMedChem

    2024  , Page(s) e202400095

    Abstract: We have assembled a computational pipeline based on virtual screening, docking techniques, and nonequilibrium molecular dynamics simulations, with the goal of identifying possible inhibitors of the SARS-CoV-2 NSP13 helicase, catalyzing by ATP hydrolysis ... ...

    Abstract We have assembled a computational pipeline based on virtual screening, docking techniques, and nonequilibrium molecular dynamics simulations, with the goal of identifying possible inhibitors of the SARS-CoV-2 NSP13 helicase, catalyzing by ATP hydrolysis the unwinding of double or single-stranded RNA in the viral replication process inside the host cell. The druggable sites for broad-spectrum inhibitors are represented by the RNA binding sites at the 5' entrance and 3' exit of the central channel, a structural motif that is highly conserved across coronaviruses. Potential binders were first generated using structure-based ligand techniques. Their potency was estimated by using four popular docking scoring functions. Common docking hits for NSP13 were finally tested using advanced nonequilibrium alchemical techniques for binding free energy calculations on a high-performing parallel cluster. Four potential NSP13 inhibitors with potency from submicrimolar to nanomolar were finally identified.
    Language English
    Publishing date 2024-03-08
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2218496-X
    ISSN 1860-7187 ; 1860-7179
    ISSN (online) 1860-7187
    ISSN 1860-7179
    DOI 10.1002/cmdc.202400095
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  2. Article ; Online: NE-RDFE: A protocol and toolkit for computing relative dissociation free energies with GROMACS between dissimilar molecules using bidirectional nonequilibrium dual topology schemes.

    Macchiagodena, Marina / Pagliai, Marco / Procacci, Piero

    Journal of computational chemistry

    2023  Volume 44, Issue 12, Page(s) 1221–1230

    Abstract: We describe a step-by-step protocol and toolkit for the computation of the relative dissociation free energy (RDFE) with the GROMACS molecular dynamics package, based on a novel bidirectional nonequilibrium alchemical approach. The proposed methodology ... ...

    Abstract We describe a step-by-step protocol and toolkit for the computation of the relative dissociation free energy (RDFE) with the GROMACS molecular dynamics package, based on a novel bidirectional nonequilibrium alchemical approach. The proposed methodology does not require any intervention on the code and allows computing with good accuracy the RDFE between small molecules with arbitrary differences in volume, charge, and chemical topology. The procedure is illustrated for the challenging SAMPL9 batch of host-guest pairs. The article is supplemented by a detailed online tutorial, available at https://procacci.github.io/vdssb_gromacs/NE-RDFE and by a public Zenodo repository available at https://zenodo.org/record/6982932.
    Language English
    Publishing date 2023-01-27
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1479181-X
    ISSN 1096-987X ; 0192-8651
    ISSN (online) 1096-987X
    ISSN 0192-8651
    DOI 10.1002/jcc.27077
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  3. Article ; Online: On the NS-DSSB unidirectional estimates in the SAMPL6 SAMPLing challenge.

    Procacci, Piero / Macchiagodena, Marina

    Journal of computer-aided molecular design

    2021  Volume 35, Issue 10, Page(s) 1055–1065

    Abstract: In the context of the recent SAMPL6 SAMPLing challenge (Rizzi et al. 2020 in J Comput Aided Mol Des 34:601-633) aimed at assessing convergence properties and reproducibility of molecular dynamics binding free energy methodologies, we propose a simple ... ...

    Abstract In the context of the recent SAMPL6 SAMPLing challenge (Rizzi et al. 2020 in J Comput Aided Mol Des 34:601-633) aimed at assessing convergence properties and reproducibility of molecular dynamics binding free energy methodologies, we propose a simple explanation of the severe errors observed in the nonequilibrium switch double-system-single-box (NS-DSSB) approach when using unidirectional estimates. At the same time, we suggest a straightforward and minimal modification of the NS-DSSB protocol for obtaining reliable unidirectional estimates for the process where the ligand is decoupled in the bound state and recoupled in the bulk.
    MeSH term(s) Algorithms ; Entropy ; Ligands ; Molecular Dynamics Simulation ; Protein Binding ; Proteins/chemistry ; Solvents/chemistry ; Thermodynamics
    Chemical Substances Ligands ; Proteins ; Solvents
    Language English
    Publishing date 2021-10-09
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 808166-9
    ISSN 1573-4951 ; 0920-654X
    ISSN (online) 1573-4951
    ISSN 0920-654X
    DOI 10.1007/s10822-021-00419-0
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  4. Article: Adsorption Geometry of Alizarin on Silver Nanoparticles: A Computational and Spectroscopic Study.

    Gellini, Cristina / Macchiagodena, Marina / Pagliai, Marco

    Nanomaterials (Basel, Switzerland)

    2021  Volume 11, Issue 4

    Abstract: The knowledge of the adsorption geometry of an analyte on a metal substrate employed in surface enhanced Raman scattering (SERS) spectroscopy is important information for the correct interpretation of experimental data. The adsorption geometry of ... ...

    Abstract The knowledge of the adsorption geometry of an analyte on a metal substrate employed in surface enhanced Raman scattering (SERS) spectroscopy is important information for the correct interpretation of experimental data. The adsorption geometry of alizarin on silver nanoparticles was studied through ab initio calculations in the framework of density functional theory (DFT) by modeling alizarin taking into account all the different charged species present in solution as a function of pH. The calculations allowed a faithful reproduction of the measured SERS spectra and to elucidate the adsorption geometry of this dye on the silver substrate.
    Language English
    Publishing date 2021-03-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662255-5
    ISSN 2079-4991
    ISSN 2079-4991
    DOI 10.3390/nano11040860
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  5. Article ; Online: Virtual Double-System Single-Box for Absolute Dissociation Free Energy Calculations in GROMACS.

    Macchiagodena, Marina / Karrenbrock, Maurice / Pagliai, Marco / Procacci, Piero

    Journal of chemical information and modeling

    2021  Volume 61, Issue 11, Page(s) 5320–5326

    Abstract: We describe a step-by-step protocol for the computation of absolute dissociation free energy with GROMACS code and PLUMED library, which exploits a combination of advanced sampling techniques and nonequilibrium alchemical methodologies. The computational ...

    Abstract We describe a step-by-step protocol for the computation of absolute dissociation free energy with GROMACS code and PLUMED library, which exploits a combination of advanced sampling techniques and nonequilibrium alchemical methodologies. The computational protocol has been automated through an open source Python middleware (HPC_Drug) which allows one to set up the GROMACS/PLUMED input files for execution on high performing computing facilities. The proposed protocol, by exploiting its inherent parallelism and the power of the GROMACS code on graphical processing units, has the potential to afford accurate and precise estimates of the dissociation constants in drug-receptor systems described at the atomistic level. The procedure has been applied to the calculation of the absolute dissociation free energy of PF-07321332, an oral antiviral proposed by Pfizer, with the main protease (3CL
    MeSH term(s) Antiviral Agents ; COVID-19 ; Entropy ; Lactams ; Leucine ; Molecular Dynamics Simulation ; Nitriles ; Proline ; SARS-CoV-2
    Chemical Substances Antiviral Agents ; Lactams ; Nitriles ; nirmatrelvir (7R9A5P7H32) ; Proline (9DLQ4CIU6V) ; Leucine (GMW67QNF9C)
    Language English
    Publishing date 2021-11-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 190019-5
    ISSN 1549-960X ; 0095-2338
    ISSN (online) 1549-960X
    ISSN 0095-2338
    DOI 10.1021/acs.jcim.1c00909
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  6. Article ; Online: Characterization of the non-covalent interaction between the PF-07321332 inhibitor and the SARS-CoV-2 main protease.

    Macchiagodena, Marina / Pagliai, Marco / Procacci, Piero

    Journal of molecular graphics & modelling

    2021  Volume 110, Page(s) 108042

    Abstract: We have studied the non-covalent interaction between PF-07321332 and SARS-CoV-2 main protease at the atomic level using a computational approach based on extensive molecular dynamics simulations with explicit solvent. PF-07321332, whose chemical ... ...

    Abstract We have studied the non-covalent interaction between PF-07321332 and SARS-CoV-2 main protease at the atomic level using a computational approach based on extensive molecular dynamics simulations with explicit solvent. PF-07321332, whose chemical structure has been recently disclosed, is a promising oral antiviral clinical candidate with well-established anti-SARS-CoV-2 activity in vitro. The drug, currently in phase III clinical trials in combination with ritonavir, relies on the electrophilic attack of a nitrile warhead to the catalytic cysteine of the protease. Nonbonded interaction between the inhibitor and the residues of the binding pocket, as well as with water molecules on the protein surface, have been characterized using two different force fields and the two possible protonation states of the main protease catalytic dyad HIS41-CYS145. When the catalytic dyad is in the neutral state, the non-covalent binding is likely to be stronger. Molecular dynamics simulations seems to lend support for an inhibitory mechanism in two steps: a first non-covalent addition with the dyad in neutral form and then the formation of the thiolate-imidazolium ion pair and the ligand relocation for finalising the electrophilic attack.
    MeSH term(s) Antiviral Agents/therapeutic use ; COVID-19 ; Coronavirus 3C Proteases ; Humans ; Lactams ; Leucine ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Nitriles ; Proline ; Protease Inhibitors ; SARS-CoV-2
    Chemical Substances Antiviral Agents ; Lactams ; Nitriles ; Protease Inhibitors ; nirmatrelvir (7R9A5P7H32) ; Proline (9DLQ4CIU6V) ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28) ; Leucine (GMW67QNF9C)
    Language English
    Publishing date 2021-10-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1396450-1
    ISSN 1873-4243 ; 1093-3263
    ISSN (online) 1873-4243
    ISSN 1093-3263
    DOI 10.1016/j.jmgm.2021.108042
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    Zs.A 3491: Show issues Location:
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  7. Article: Identification of potential binders of the main protease 3CL

    Macchiagodena, Marina / Pagliai, Marco / Procacci, Piero

    Chemical physics letters

    2020  Volume 750, Page(s) 137489

    Abstract: We have applied a computational strategy, using a combination of virtual screening, docking and molecular dynamics techniques, aimed at identifying possible lead compounds for the non-covalent inhibition of the main protease ... ...

    Abstract We have applied a computational strategy, using a combination of virtual screening, docking and molecular dynamics techniques, aimed at identifying possible lead compounds for the non-covalent inhibition of the main protease 3CL
    Keywords covid19
    Language English
    Publishing date 2020-04-18
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 1466293-0
    ISSN 0009-2614
    ISSN 0009-2614
    DOI 10.1016/j.cplett.2020.137489
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  8. Article ; Online: Adsorption Geometry of Alizarin on Silver Nanoparticles

    Cristina Gellini / Marina Macchiagodena / Marco Pagliai

    Nanomaterials, Vol 11, Iss 860, p

    A Computational and Spectroscopic Study

    2021  Volume 860

    Abstract: The knowledge of the adsorption geometry of an analyte on a metal substrate employed in surface enhanced Raman scattering (SERS) spectroscopy is important information for the correct interpretation of experimental data. The adsorption geometry of ... ...

    Abstract The knowledge of the adsorption geometry of an analyte on a metal substrate employed in surface enhanced Raman scattering (SERS) spectroscopy is important information for the correct interpretation of experimental data. The adsorption geometry of alizarin on silver nanoparticles was studied through ab initio calculations in the framework of density functional theory (DFT) by modeling alizarin taking into account all the different charged species present in solution as a function of pH. The calculations allowed a faithful reproduction of the measured SERS spectra and to elucidate the adsorption geometry of this dye on the silver substrate.
    Keywords Alizarin ; Raman spectroscopy ; SERS ; silver nanoparticles ; DFT calculations ; Chemistry ; QD1-999
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: 2-Butanol Aqueous Solutions: A Combined Molecular Dynamics and Small/Wide-Angle X-ray Scattering Study.

    Macchiagodena, Marina / Bassu, Gavino / Vettori, Irene / Fratini, Emiliano / Procacci, Piero / Pagliai, Marco

    The journal of physical chemistry. A

    2022  Volume 126, Issue 47, Page(s) 8826–8833

    Abstract: Structural properties of 2-butanol aqueous solutions at different concentrations have been studied using small- and wide-angle X-ray scattering and molecular dynamics simulations. The experimental structure factors have been accurately reproduced by the ... ...

    Abstract Structural properties of 2-butanol aqueous solutions at different concentrations have been studied using small- and wide-angle X-ray scattering and molecular dynamics simulations. The experimental structure factors have been accurately reproduced by the simulations, allowing one to explain their variation with concentration and to achieve a detailed description of the structural and dynamic properties of the studied systems. The analysis of experimental and computational data has shown that 2-butanol, the simplest aliphatic chiral alcohol, tends to form aggregates at a concentration above 1 M, affecting also both the structural and dynamic properties of the solvent.
    MeSH term(s) Molecular Dynamics Simulation ; X-Rays ; Butanols ; Solvents
    Chemical Substances 2-butanol (0TUL3ENK62) ; Butanols ; Solvents
    Language English
    Publishing date 2022-11-17
    Publishing country United States
    Document type Journal Article
    ISSN 1520-5215
    ISSN (online) 1520-5215
    DOI 10.1021/acs.jpca.2c05708
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  10. Article ; Online: Upgrading of the general AMBER force field 2 for fluorinated alcohol biosolvents: A validation for water solutions and melittin solvation.

    Casoria, Michele / Macchiagodena, Marina / Rovero, Paolo / Andreini, Claudia / Papini, Anna Maria / Cardini, Gianni / Pagliai, Marco

    Journal of peptide science : an official publication of the European Peptide Society

    2023  Volume 30, Issue 2, Page(s) e3543

    Abstract: The standard GAFF2 force field parameterization has been refined for the fluorinated alcohols 2,2,2-trifluoroethanol (TFE), 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), and 1,1,1,3,3,3-hexafluoropropan-2-one (HFA), which are commonly used to study proteins ... ...

    Abstract The standard GAFF2 force field parameterization has been refined for the fluorinated alcohols 2,2,2-trifluoroethanol (TFE), 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), and 1,1,1,3,3,3-hexafluoropropan-2-one (HFA), which are commonly used to study proteins and peptides in biomimetic media. The structural and dynamic properties of both proteins and peptides are significantly influenced by the biomimetic environment created by the presence of these cosolvents in aqueous solutions. Quantum mechanical calculations on stable conformers were used to parameterize the atomic charges. Different systems, such as pure liquids, aqueous solutions, and systems formed by melittin protein and cosolvent/water solutions, have been used to validate the new models. The calculated macroscopic and structural properties are in agreement with experimental findings, supporting the validity of the newly proposed models.
    MeSH term(s) Melitten/chemistry ; Solvents/chemistry ; Alcohols/chemistry ; Peptides/chemistry ; Proteins/chemistry ; Water/chemistry ; Trifluoroethanol/chemistry
    Chemical Substances Melitten (20449-79-0) ; Solvents ; Alcohols ; Peptides ; Proteins ; Water (059QF0KO0R) ; Trifluoroethanol (75-89-8)
    Language English
    Publishing date 2023-09-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 1234416-3
    ISSN 1099-1387 ; 1075-2617
    ISSN (online) 1099-1387
    ISSN 1075-2617
    DOI 10.1002/psc.3543
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