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Book ; Online: Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein (Topology and .xtc files)

Giuseppe Deganutti

2020

Abstract: ABSTRACT. The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting ... ...

Abstract	ABSTRACT. The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs approved for other diseases. The first interaction between the virus and the host cell is mediated by the spike protein on the virus surface and the human angiotensin-converting enzyme (ACE2). Small molecules able to bind the receptor-binding domain (RBD) of the spike protein and disrupt the binding to ACE2 would offer an important tool for slowing, or even preventing, the infection. Here, we screened 2421 approved small molecules in silico and validated the docking outcomes through extensive molecular dynamics simulations. Out of six drugs characterized as putative RBD binders, the cephalosporin antibiotic cefsulodin was further assessed for its effect on the binding between the RBD and ACE2, suggesting the importance of considering the dynamic formation of the heterodimer when judging any potential candidate.
Keywords	SARS-CoV-2 ; COVID-19 ; drug repurposing ; spike protein ; molecular dynamics ; supervised molecular dynamics ; covid19
Subject code	612
Publishing date	2020-10-09
Publishing country	eu
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Targeting hPKM2 in cancer: A bio isosteric approach for ligand design.

Pipitò, Ludovico / Illingworth, Thomas Arron / Deganutti, Giuseppe

Computers in biology and medicine

2023 Volume 158, Page(s) 106852

Abstract: The term cancer refers to a plethora of diseases characterized by the development of abnormal cells that divide uncontrollably and can infiltrate further proximal or distal body tissues. Each type of cancer can be defined by aggressiveness, localization, ...

Abstract	The term cancer refers to a plethora of diseases characterized by the development of abnormal cells that divide uncontrollably and can infiltrate further proximal or distal body tissues. Each type of cancer can be defined by aggressiveness, localization, metabolism, and response to available treatments. Among the most common hallmarks of cancer is a more acidic intracellular microenvironment. Offset pH values are due to an excess of lactate and an increased hypoxia-inducible factor (HIF) expression, which leads to a hypoxic state and a metabolic shift towards glycolysis to produce adenosine-5'-triphosphate (ATP) necessary for cellular metabolism. Warburg's hypothesis underpins this concept, making glycolysis and its central enzyme pyruvate kinase (hPKM2), an ideal target for drug development. Using molecular docking and extensive molecular dynamics (MD) simulations we investigated the binding mode of phosphoenolpyruvate (PEP) inside the hPKM2 active site, and then evaluated a set of known bio-isosteric inhibitors to understand the differences caused by their substitutions on their binding mode. Ultimately, we propose a new molecular entity to hamper hPKM2, unbalance cellular energy, and possibly trigger autophagic mechanisms.
MeSH term(s)	Humans ; Ligands ; Molecular Docking Simulation ; Neoplasms/metabolism ; Glycolysis ; Adenosine Triphosphate ; Tumor Microenvironment
Chemical Substances	Ligands ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2023-04-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	127557-4
ISSN	1879-0534 ; 0010-4825
ISSN (online)	1879-0534
ISSN	0010-4825
DOI	10.1016/j.compbiomed.2023.106852
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Article ; Online: Computational Insights into the Conformational Dynamics of HIV-1 Vpr in a Lipid Bilayer for Ion Channel Modeling.

Majumder, Satyabrata / Deganutti, Giuseppe / Pipitò, Ludovico / Chaudhuri, Dwaipayan / Datta, Joyeeta / Giri, Kalyan

Journal of chemical information and modeling

2024 Volume 64, Issue 8, Page(s) 3360–3374

Abstract: HIV-1 Vpr is a multifunctional accessory protein consisting of 96 amino acids that play a critical role in viral pathogenesis. Among its diverse range of activities, Vpr can create a cation-selective ion channel within the plasma membrane. However, the ... ...

Abstract	HIV-1 Vpr is a multifunctional accessory protein consisting of 96 amino acids that play a critical role in viral pathogenesis. Among its diverse range of activities, Vpr can create a cation-selective ion channel within the plasma membrane. However, the oligomeric state of this channel has not yet been elucidated. In this study, we investigated the conformational dynamics of Vpr helices to model the ion channel topology. First, we employed a series of multiscale simulations to investigate the specific structure of monomeric Vpr in a membrane model. During the lipid bilayer self-assembly coarse grain simulation, the C-terminal helix (residues 56-77) effectively formed the transmembrane region, while the N-terminal helix exhibited an amphipathic nature by associating horizontally with a single leaflet. All-atom molecular dynamics (MD) simulations of full-length Vpr inside a phospholipid bilayer show that the C-terminal helix remains very stable inside the bilayer core in a vertical orientation. Subsequently, using the predicted C-terminal helix orientation and conformation, various oligomeric states (ranging from tetramer to heptamer) possibly forming the Vpr ion channel were built and further evaluated. Among these models, the pentameric form exhibited consistent stability in MD simulations and displayed a compatible conformation for a water-assisted ion transport mechanism. This study provides structural insights into the ion channel activity of the Vpr protein and the foundation for developing therapeutics against HIV-1 Vpr-related conditions.
MeSH term(s)	Molecular Dynamics Simulation ; Lipid Bilayers/chemistry ; Lipid Bilayers/metabolism ; vpr Gene Products, Human Immunodeficiency Virus/chemistry ; vpr Gene Products, Human Immunodeficiency Virus/metabolism ; Ion Channels/chemistry ; Ion Channels/metabolism ; Protein Conformation ; HIV-1/chemistry
Chemical Substances	Lipid Bilayers ; vpr Gene Products, Human Immunodeficiency Virus ; Ion Channels ; vpr protein, Human immunodeficiency virus 1
Language	English
Publishing date	2024-04-10
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.3c01859
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Article ; Online: Is the Stalk of the SARS-CoV-2 Spike Protein Druggable?

Pipitò, Ludovico / Reynolds, Christopher A / Deganutti, Giuseppe

Viruses

2022 Volume 14, Issue 12

Abstract: The spike protein is key to SARS-CoV-2 high infectivity because it facilitates the receptor binding domain (RBD) encounter with ACE2. As targeting subunit S1 has not yet delivered an ACE2-binding inhibitor, we have assessed the druggability of the ... ...

Abstract	The spike protein is key to SARS-CoV-2 high infectivity because it facilitates the receptor binding domain (RBD) encounter with ACE2. As targeting subunit S1 has not yet delivered an ACE2-binding inhibitor, we have assessed the druggability of the conserved segment of the spike protein stalk within subunit S2 by means of an integrated computational approach that combines the molecular docking of an optimized library of fragments with high-throughput molecular dynamics simulations. The high propensity of the spike protein to mutate in key regions that are responsible for the recognition of the human angiotensin-converting enzyme 2 (hACE2) or for the recognition of antibodies, has made subunit S1 of the spike protein difficult to target. Despite the inherent flexibility of the stalk region, our results suggest two hidden interhelical binding sites, whose accessibility is only partially hampered by glycan residues.
MeSH term(s)	Humans ; COVID-19 ; Spike Glycoprotein, Coronavirus/metabolism ; SARS-CoV-2/metabolism ; Angiotensin-Converting Enzyme 2/metabolism ; Molecular Docking Simulation ; Protein Domains ; Protein Binding ; Molecular Dynamics Simulation
Chemical Substances	spike protein, SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2022-12-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v14122789
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Molecular dynamics studies reveal structural and functional features of the SARS-CoV-2 spike protein.

Pipitò, Ludovico / Rujan, Roxana-Maria / Reynolds, Christopher A / Deganutti, Giuseppe

BioEssays : news and reviews in molecular, cellular and developmental biology

2022 Volume 44, Issue 9, Page(s) e2200060

Abstract: The SARS-CoV-2 virus is responsible for the COVID-19 pandemic the world experience since 2019. The protein responsible for the first steps of cell invasion, the spike protein, has probably received the most attention in light of its central role during ... ...

Abstract	The SARS-CoV-2 virus is responsible for the COVID-19 pandemic the world experience since 2019. The protein responsible for the first steps of cell invasion, the spike protein, has probably received the most attention in light of its central role during infection. Computational approaches are among the tools employed by the scientific community in the enormous effort to study this new affliction. One of these methods, namely molecular dynamics (MD), has been used to characterize the function of the spike protein at the atomic level and unveil its structural features from a dynamic perspective. In this review, we focus on these main findings, including spike protein flexibility, rare S protein conformational changes, cryptic epitopes, the role of glycans, drug repurposing, and the effect of spike protein variants.
MeSH term(s)	COVID-19 ; Humans ; Molecular Dynamics Simulation ; Pandemics ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-07-17
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	50140-2
ISSN	1521-1878 ; 0265-9247
ISSN (online)	1521-1878
ISSN	0265-9247
DOI	10.1002/bies.202200060
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Article ; Online: Computer-aided de novo design and optimization of novel potential inhibitors of HIV-1 Nef protein.

Majumder, Satyabrata / Deganutti, Giuseppe / Pipitò, Ludovico / Chaudhuri, Dwaipayan / Datta, Joyeeta / Giri, Kalyan

Computational biology and chemistry

2023 Volume 104, Page(s) 107871

Abstract: Nef is a small accessory protein pivotal in the HIV-1 viral replication cycle. It is a multifunctional protein and its interactions with kinases in host cells have been well characterized through many in vitro and structural studies. Nef forms a ... ...

Abstract	Nef is a small accessory protein pivotal in the HIV-1 viral replication cycle. It is a multifunctional protein and its interactions with kinases in host cells have been well characterized through many in vitro and structural studies. Nef forms a homodimer to activate the kinases and subsequently the phosphorylation pathways. The disruption of its homodimerization represents a valuable approach in the search for novel classes of antiretroviral. However, this research avenue is still underdeveloped as just a few Nef inhibitors have been reported so far, with very limited structural information about their mechanism of action. To address this issue, we have employed an in silico structure-based drug design strategy that combines de novo ligand design with molecular docking and extensive molecular dynamics simulations. Since the Nef pocket involved in homodimerization has high lipophilicity, the initial de novo-designed structures displayed poor drug-likeness and solubility. Taking information from the hydration sites within the homodimerization pocket, structural modifications in the initial lead compound have been introduced to improve the solubility and drug-likeness, without affecting the binding profile. We propose lead compounds that can be the starting point for further optimizations to deliver long-awaited, rationally designed Nef inhibitors.
MeSH term(s)	Molecular Docking Simulation ; HIV-1 ; Computer-Aided Design ; Gene Products, nef ; Computers
Chemical Substances	Gene Products, nef
Language	English
Publishing date	2023-04-15
Publishing country	England
Document type	Journal Article
ISSN	1476-928X
ISSN (online)	1476-928X
DOI	10.1016/j.compbiolchem.2023.107871
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Multisite Model of Allosterism for the Adenosine A1 Receptor.

Deganutti, Giuseppe / Barkan, Kerry / Ladds, Graham / Reynolds, Christopher A

Journal of chemical information and modeling

2021 Volume 61, Issue 4, Page(s) 2001–2015

Abstract: Despite being a target for about one-third of approved drugs, G protein-coupled receptors (GPCRs) still represent a tremendous reservoir for therapeutic strategies against diseases. For example, several cardiovascular and central nervous system ... ...

Abstract	Despite being a target for about one-third of approved drugs, G protein-coupled receptors (GPCRs) still represent a tremendous reservoir for therapeutic strategies against diseases. For example, several cardiovascular and central nervous system conditions could benefit from clinical agents that activate the adenosine 1 receptor (A
Language	English
Publishing date	2021-03-29
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.0c01331
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Article ; Online: Understanding The Role of Heparinoids on the SARS-CoV-2 Spike Protein through Molecular Dynamics Simulations

Pipito, Ludovico / Reynolds, Christopher A / Deganutti, Giuseppe

bioRxiv

Abstract: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a threat, with an estimated number of deaths exceeding 5 million. SARS-CoV-2 entry into the cell is mediated by its transmembrane spike glycoprotein (S ... ...

Abstract	The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a threat, with an estimated number of deaths exceeding 5 million. SARS-CoV-2 entry into the cell is mediated by its transmembrane spike glycoprotein (S protein), and the angiotensin-converting enzyme 2 (ACE2) receptor on the human cell surface. The extracellular heparan sulphate (ecHS) enhances the S protein binding through a mechanism still unknown. Surprisingly, low molecular weight heparin (LMWH) and HS in the disaccharide form (dHS) hinder the S protein binding to ACE2, despite the similarity with ecHS. We investigated the molecular mechanism behind this inhibition through molecular dynamics (MD) simulations to understand the interaction pattern of the heparinoids with S protein and the ACE2 receptor.
Keywords	covid19
Language	English
Publishing date	2022-07-06
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.07.05.498807
Database	COVID19

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Article ; Online: Is The Stalk of the SARS-CoV-2 Spike Protein Druggable?

Pipito, Ludovico / Reynolds, Christopher A. / Deganutti, Giuseppe

bioRxiv

Abstract: The SARS-CoV-2 virus spike protein (SP) is the vector of the virus infectivity. The high propensity to mutate in key regions responsible for the recognition of the human angiotensin-converting enzyme 2 (hACE2) or the antibodies produced by the immune ... ...

Abstract	The SARS-CoV-2 virus spike protein (SP) is the vector of the virus infectivity. The high propensity to mutate in key regions responsible for the recognition of the human angiotensin-converting enzyme 2 (hACE2) or the antibodies produced by the immune system following infection or vaccination makes subunit 1 of the SP a difficult to target and, to date, efforts have not delivered any ACE2 binding inhibitor yet. The inherent flexibility of the stalk region, within subunit S2, is key to SARS-CoV-2 high infectivity because it facilitates the receptor binding domain encounter with ACE2. Thus, it could be a valuable therapeutic target. By employing a fragment-based strategy, we computationally studied the druggability of the conserved part of the SP stalk by means of an integrated approach that combines molecular docking with high-throughput molecular dynamics simulations. Our results suggest that the druggability of the stalk is challenging and provide the structural basis for such difficulty.
Keywords	covid19
Language	English
Publishing date	2022-10-06
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.10.06.511069
Database	COVID19

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Article ; Online: A Supervised Molecular Dynamics Approach to Unbiased Ligand-Protein Unbinding.

Deganutti, Giuseppe / Moro, Stefano / Reynolds, Christopher A

Journal of chemical information and modeling

2020 Volume 60, Issue 3, Page(s) 1804–1817

Abstract: The recent paradigm shift toward the use of the kinetics parameters in place of thermodynamic constants is leading the computational chemistry community to develop methods for studying the mechanisms of drug binding and unbinding. From this standpoint, ... ...

Abstract	The recent paradigm shift toward the use of the kinetics parameters in place of thermodynamic constants is leading the computational chemistry community to develop methods for studying the mechanisms of drug binding and unbinding. From this standpoint, molecular dynamics (MD) plays an important role in delivering insight at the molecular scale. However, a known limitation of MD is that the time scales are usually far from those involved in ligand-receptor unbinding events. Here, we show that the algorithm behind supervised MD (SuMD) can simulate the dissociation mechanism of druglike small molecules while avoiding the input of any energy bias to facilitate the transition. SuMD was tested on seven different intermolecular complexes, covering four G protein-coupled receptors: the A
MeSH term(s)	Kinetics ; Ligands ; Molecular Dynamics Simulation ; Protein Binding ; Thermodynamics
Chemical Substances	Ligands
Language	English
Publishing date	2020-03-09
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.9b01094
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