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Special Issue "Exscalate4CoV: Innovative High Performing Computing (HPC) Strategies to Tackle Pandemic Crisis"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Informatics".

Deadline for manuscript submissions: 31 March 2022.

Special Issue Editors

Prof. Dr. Giulio Vistoli
E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences Università degli Studi di Milano, via Mangiagalli 25, 20133 Milano, Italy
Interests: computational chemistry; drug design; cheminformatics; molecular docking; ADME predictions; lipophilicity
Special Issues and Collections in MDPI journals
Dr. Andrea Beccari
E-Mail Website
Guest Editor
Head of R&D Platforms & Services, Dompé farmaceutici S.p.A. - Via Pietro Castellino, 111 - 80131 Napoli, Italy
Interests: rational drug design; virtual screening; predictive medicine; polypharmacology; quantitative system pharmacology; enumeration/annotation & bio-profiling of the synthesizable chemical space

Special Issue Information

Dear Colleagues,

The EXSCALATE4CoV (E4C) project aims to exploit the most powerful computing resources currently based in Europe to empower smart in silico drug design. Advanced computer-aided drug design (CADD) in combination with high-throughput biochemical and phenotypic screening will allow the rapid evaluation of the performed simulations and the reduction of time for the discovery of new drugs. Against a pandemic crisis, the rapid identification of effective treatments has indeed a dramatic relevance. E4C is mostly based on the already developed and validated EXSCALATE docking platform and its activities will be supported and empowered by three of the most powerful computer centers in Europe: CINECA, BSC, and JÜLICH. The E4C project will promptly disseminate its scientific outcomes to the research community, sharing all computational results and produced data trhough dedicated repositories. Thus, this Special Issue is intended as an E4C dissemination forum where all the obtained computational results will be carefully described with a view to fostering the deployment of the shared data for novel independent studies. Hence, all research groups which exploit the E4C shared outcomes for their own research are warmly invited to contribute to this Special Issue in order to achive a comprehensive picture of the various applications the shared data can offer and of the thus-obtained results.

For more details about E4C project, please see the following page:

https://www.exscalate4cov.eu/

Prof. Dr. Giulio Vistoli
Dr. Andrea Beccari
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Coronavirus
  • Pandemic crisis
  • In silico drug design
  • Virtual screening
  • Homologous models
  • Molecular dynamics
  • Drug repurposing
  • High-performing computing

Published Papers (5 papers)

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Research

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Article
Altered Local Interactions and Long-Range Communications in UK Variant (B.1.1.7) Spike Glycoprotein
Int. J. Mol. Sci. 2021, 22(11), 5464; https://doi.org/10.3390/ijms22115464 - 22 May 2021
Viewed by 541
Abstract
The COVID-19 pandemic is caused by SARS-CoV-2. Currently, most of the research efforts towards the development of vaccines and antibodies against SARS-CoV-2 were mainly focused on the spike (S) protein, which mediates virus entry into the host cell by binding to ACE2. As [...] Read more.
The COVID-19 pandemic is caused by SARS-CoV-2. Currently, most of the research efforts towards the development of vaccines and antibodies against SARS-CoV-2 were mainly focused on the spike (S) protein, which mediates virus entry into the host cell by binding to ACE2. As the virus SARS-CoV-2 continues to spread globally, variants have emerged, characterized by multiple mutations of the S glycoprotein. Herein, we employed microsecond-long molecular dynamics simulations to study the impact of the mutations of the S glycoprotein in SARS-CoV-2 Variant of Concern 202012/01 (B.1.1.7), termed the “UK variant”, in comparison with the wild type, with the aim to decipher the structural basis of the reported increased infectivity and virulence. The simulations provided insights on the different dynamics of UK and wild-type S glycoprotein, regarding in particular the Receptor Binding Domain (RBD). In addition, we investigated the role of glycans in modulating the conformational transitions of the RBD. The overall results showed that the UK mutant experiences higher flexibility in the RBD with respect to wild type; this behavior might be correlated with the increased transmission reported for this variant. Our work also adds useful structural information on antigenic “hotspots” and epitopes targeted by neutralizing antibodies. Full article
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Article
Multiple Recombination Events and Strong Purifying Selection at the Origin of SARS-CoV-2 Spike Glycoprotein Increased Correlated Dynamic Movements
Int. J. Mol. Sci. 2021, 22(1), 80; https://doi.org/10.3390/ijms22010080 - 23 Dec 2020
Cited by 6 | Viewed by 1525
Abstract
Our evolutionary and structural analyses revealed that the severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) spike gene is a complex mosaic resulting from several recombination events. Additionally, the fixation of variants has mainly been driven by purifying selection, suggesting the presence of [...] Read more.
Our evolutionary and structural analyses revealed that the severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) spike gene is a complex mosaic resulting from several recombination events. Additionally, the fixation of variants has mainly been driven by purifying selection, suggesting the presence of conserved structural features. Our dynamic simulations identified two main long-range covariant dynamic movements of the novel glycoprotein, and showed that, as a result of the evolutionary duality, they are preserved. The first movement involves the receptor binding domain with the N-terminal domain and the C-terminal domain 2 and is maintained across human, bat and pangolin coronaviruses. The second is a complex network of long-range dynamics specific to SARS-CoV-2 involving the novel PRRA and the conserved KR*SF cleavage sites, as well as conserved segments in C-terminal domain 3. These movements, essential for host cell binding, are maintained by hinges conserved across human, bat, and pangolin coronaviruses glycoproteins. The hinges, located around Threonine 333 and Proline 527 within the N-terminal domain and C-terminal domain 2, represent candidate targets for the future development of novel pan-coronavirus inhibitors. In summary, we show that while recombination created a new configuration that increased the covariant dynamic movements of the SARS-CoV-2 glycoprotein, negative selection preserved its inter-domain structure throughout evolution in different hosts and inter-species transmissions. Full article
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Article
Computational Studies of SARS-CoV-2 3CLpro: Insights from MD Simulations
Int. J. Mol. Sci. 2020, 21(15), 5346; https://doi.org/10.3390/ijms21155346 - 28 Jul 2020
Cited by 14 | Viewed by 2162
Abstract
Given the enormous social and health impact of the pandemic triggered by severe acute respiratory syndrome 2 (SARS-CoV-2), the scientific community made a huge effort to provide an immediate response to the challenges posed by Coronavirus disease 2019 (COVID-19). One of the most [...] Read more.
Given the enormous social and health impact of the pandemic triggered by severe acute respiratory syndrome 2 (SARS-CoV-2), the scientific community made a huge effort to provide an immediate response to the challenges posed by Coronavirus disease 2019 (COVID-19). One of the most important proteins of the virus is an enzyme, called 3CLpro or main protease, already identified as an important pharmacological target also in SARS and Middle East respiratory syndrome virus (MERS) viruses. This protein triggers the production of a whole series of enzymes necessary for the virus to carry out its replicating and infectious activities. Therefore, it is crucial to gain a deeper understanding of 3CLpro structure and function in order to effectively target this enzyme. All-atoms molecular dynamics (MD) simulations were performed to examine the different conformational behaviors of the monomeric and dimeric form of SARS-CoV-2 3CLpro apo structure, as revealed by microsecond time scale MD simulations. Our results also shed light on the conformational dynamics of the loop regions at the entry of the catalytic site. Studying, at atomic level, the characteristics of the active site and obtaining information on how the protein can interact with its substrates will allow the design of molecules able to block the enzymatic function crucial for the virus. Full article
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Article
A Comprehensive Mapping of the Druggable Cavities within the SARS-CoV-2 Therapeutically Relevant Proteins by Combining Pocket and Docking Searches as Implemented in Pockets 2.0
Int. J. Mol. Sci. 2020, 21(14), 5152; https://doi.org/10.3390/ijms21145152 - 21 Jul 2020
Cited by 9 | Viewed by 1890
Abstract
(1) Background: Virtual screening studies on the therapeutically relevant proteins of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) require a detailed characterization of their druggable binding sites, and, more generally, a convenient pocket mapping represents a key step for structure-based in silico [...] Read more.
(1) Background: Virtual screening studies on the therapeutically relevant proteins of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) require a detailed characterization of their druggable binding sites, and, more generally, a convenient pocket mapping represents a key step for structure-based in silico studies; (2) Methods: Along with a careful literature search on SARS-CoV-2 protein targets, the study presents a novel strategy for pocket mapping based on the combination of pocket (as performed by the well-known FPocket tool) and docking searches (as performed by PLANTS or AutoDock/Vina engines); such an approach is implemented by the Pockets 2.0 plug-in for the VEGA ZZ suite of programs; (3) Results: The literature analysis allowed the identification of 16 promising binding cavities within the SARS-CoV-2 proteins and the here proposed approach was able to recognize them showing performances clearly better than those reached by the sole pocket detection; and (4) Conclusions: Even though the presented strategy should require more extended validations, this proved successful in precisely characterizing a set of SARS-CoV-2 druggable binding pockets including both orthosteric and allosteric sites, which are clearly amenable for virtual screening campaigns and drug repurposing studies. All results generated by the study and the Pockets 2.0 plug-in are available for download. Full article
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Review

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Review
SARS-CoV-2 Entry Inhibitors: Small Molecules and Peptides Targeting Virus or Host Cells
Int. J. Mol. Sci. 2020, 21(16), 5707; https://doi.org/10.3390/ijms21165707 - 09 Aug 2020
Cited by 19 | Viewed by 3097
Abstract
The pandemic evolution of SARS-CoV-2 infection is forcing the scientific community to unprecedented efforts to explore all possible approaches against COVID-19. In this context, targeting virus entry is a promising antiviral strategy for controlling viral infections. The main strategies pursued to inhibit the [...] Read more.
The pandemic evolution of SARS-CoV-2 infection is forcing the scientific community to unprecedented efforts to explore all possible approaches against COVID-19. In this context, targeting virus entry is a promising antiviral strategy for controlling viral infections. The main strategies pursued to inhibit the viral entry are considering both the virus and the host factors involved in the process. Primarily, direct-acting antivirals rely on inhibition of the interaction between ACE2 and the receptor binding domain (RBD) of the Spike (S) protein or targeting the more conserved heptad repeats (HRs), involved in the membrane fusion process. The inhibition of host TMPRSS2 and cathepsins B/L may represent a complementary strategy to be investigated. In this review, we discuss the development entry inhibitors targeting the S protein, as well as the most promising host targeting strategies involving TMPRSS2 and CatB/L, which have been exploited so far against CoVs and other related viruses. Full article
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