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Chasing New Therapeutics for COVID-19: Target Identification and Validation, Medicinal...
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Chasing New Therapeutics for COVID-19: Target Identification and Validation, Medicinal Chemistry and Drug Discovery Efforts

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 20388

Special Issue Editors

Dr. Margherita Brindisi

E-Mail Website
Guest Editor
Department of Pharmacy, University of Naples ‘Federico II’, Naples, Italy
Interests: medicinal chemistry; drug discovery; drug repurposing/repositioning; structure–activity relationships; antiviral agents; antibacterials; anticancer agents; protease inhibitors; therapeutics for rare diseases
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Mark Brönstrup

E-Mail Website
Guest Editor
Department of Chemical Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
Interests: drug discovery; antivirals; antibiotics; mass spectrometry; infectious diseases; metabolomics; lead discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over the last 20 years coronaviruses (CoVs) such as SARS-CoV, MERS-CoV and, lastly, SARS-CoV-2 (the etiological agent of COVID-19 disease) have recurrently emerged from animal reservoirs, causing outbreaks of severe respiratory syndromes in humans. COVID-19 represents the worst pandemic in the past 100 years, having triggered thus far about 100 million confirmed cases and >2 million deaths. Throughout 2020 the scientific community has been ramping-up efforts to identify COVID-19 treatments. Repurposed drugs, vaccines and antibody-based therapies have reached the clinic at an unprecedented speed. Mass vaccination campaigns have started on a global scale, but there are uncertainties concerning the duration of the vaccine-induced immunity and the efficacy that current vaccines may have against future CoV variants. As the world found itself quite unprepared in terms of antiviral drug armamentarium, broad-spectrum antivirals against current or future CoVs represent a valuable weapon of extreme medical and social importance.

In this Special Issue, we would like to provide an in depth look on potential targets, strategies for rational drug design, examples of hit/lead generation and optimization and recent medicinal chemistry efforts toward the evolution of small molecules acting as potential therapeutics against SARS-CoV-2. We also welcome studies on natural or nature-inspired derivatives as COVID-19 therapeutics. Likewise, concise review articles highlighting state-of-the-art in the field will be appreciated. Rather than just compiling a Special Issue we would like to use the opportunities offered by an Open Access Journal platform to further stimulate drug design and discovery efforts toward the development of novel therapeutic options tackling COVID-19 and future pathogenic CoVs.

Dr. Margherita Brindisi
Prof. Dr. Mark Brönstrup
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 submissions that pass pre-check are 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. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • Antiviral agents
  • Medicinal chemistry
  • Target identification
  • Target validation
  • Drug repurposing/repositioning
  • Computational chemistry
  • Small molecules
  • Peptidomimetics
  • Privileged structures
  • Natural compounds

Published Papers (5 papers)

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Research

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15 pages, 7582 KiB  
Article
Computational Study of SARS-CoV-2 RNA Dependent RNA Polymerase Allosteric Site Inhibition
by Shah Faisal, Syed Lal Badshah, Bibi Kubra, Mohamed Sharaf, Abdul-Hamid Emwas, Mariusz Jaremko and Mohnad Abdalla
Molecules 2022, 27(1), 223; https://doi.org/10.3390/molecules27010223 - 30 Dec 2021
Cited by 17 | Viewed by 2885
Abstract
The COVID-19 pandemic has caused millions of fatalities since 2019. Despite the availability of vaccines for this disease, new strains are causing rapid ailment and are a continuous threat to vaccine efficacy. Here, molecular docking and simulations identify strong inhibitors of the allosteric [...] Read more.
The COVID-19 pandemic has caused millions of fatalities since 2019. Despite the availability of vaccines for this disease, new strains are causing rapid ailment and are a continuous threat to vaccine efficacy. Here, molecular docking and simulations identify strong inhibitors of the allosteric site of the SARS-CoV-2 virus RNA dependent RNA polymerase (RdRp). More than one hundred different flavonoids were docked with the SARS-CoV-2 RdRp allosteric site through computational screening. The three top hits were Naringoside, Myricetin and Aureusidin 4,6-diglucoside. Simulation analyses confirmed that they are in constant contact during the simulation time course and have strong association with the enzyme’s allosteric site. Absorption, distribution, metabolism, excretion and toxicity (ADMET) data provided medicinal information of these top three hits. They had good human intestinal absorption (HIA) concentrations and were non-toxic. Due to high mutation rates in the active sites of the viral enzyme, these new allosteric site inhibitors offer opportunities to drug SARS-CoV-2 RdRp. These results provide new information for the design of novel allosteric inhibitors against SARS-CoV-2 RdRp. Full article
(This article belongs to the Special Issue Chasing New Therapeutics for COVID-19: Target Identification and Validation, Medicinal Chemistry and Drug Discovery Efforts)
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14 pages, 4519 KiB  
Article
l-Arginine Improves Solubility and ANTI SARS-CoV-2 Mpro Activity of Rutin but Not the Antiviral Activity in Cells
by Luca Sancineto, Carmine Ostacolo, David Ortega-Alarcon, Ana Jimenez-Alesanco, Laura Ceballos-Laita, Sonia Vega, Olga Abian, Adrian Velazquez-Campoy, Silvia Moretti, Agnieszka Dabrowska, Pawel Botwina, Aleksandra Synowiec, Anna Kula-Pacurar, Krzysztof Pyrc, Nunzio Iraci and Claudio Santi
Molecules 2021, 26(19), 6062; https://doi.org/10.3390/molecules26196062 - 07 Oct 2021
Cited by 5 | Viewed by 3906
Abstract
The COVID-19 pandemic outbreak prompts an urgent need for efficient therapeutics, and repurposing of known drugs has been extensively used in an attempt to get to anti-SARS-CoV-2 agents in the shortest possible time. The glycoside rutin shows manifold pharmacological activities and, despite its [...] Read more.
The COVID-19 pandemic outbreak prompts an urgent need for efficient therapeutics, and repurposing of known drugs has been extensively used in an attempt to get to anti-SARS-CoV-2 agents in the shortest possible time. The glycoside rutin shows manifold pharmacological activities and, despite its use being limited by its poor solubility in water, it is the active principle of many pharmaceutical preparations. We herein report our in silico and experimental investigations of rutin as a SARS-CoV-2 Mpro inhibitor and of its water solubility improvement obtained by mixing it with l-arginine. Tests of the rutin/l-arginine mixture in a cellular model of SARS-CoV-2 infection highlighted that the mixture still suffers from unfavorable pharmacokinetic properties, but nonetheless, the results of this study suggest that rutin might be a good starting point for hit optimization. Full article
(This article belongs to the Special Issue Chasing New Therapeutics for COVID-19: Target Identification and Validation, Medicinal Chemistry and Drug Discovery Efforts)
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16 pages, 5277 KiB  
Article
Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors
by Arun K. Ghosh, Dana Shahabi, Monika Yadav, Satish Kovela, Brandon J. Anson, Emma K. Lendy, Connie Bonham, Devika Sirohi, Carlos A. Brito-Sierra, Shin-ichiro Hattori, Richard Kuhn, Hiroaki Mitsuya and Andrew D. Mesecar
Molecules 2021, 26(19), 5782; https://doi.org/10.3390/molecules26195782 - 24 Sep 2021
Cited by 9 | Viewed by 3504
Abstract
We report the design and synthesis of a series of new 5-chloropyridinyl esters of salicylic acid, ibuprofen, indomethacin, and related aromatic carboxylic acids for evaluation against SARS-CoV-2 3CL protease enzyme. These ester derivatives were synthesized using EDC in the presence of DMAP to [...] Read more.
We report the design and synthesis of a series of new 5-chloropyridinyl esters of salicylic acid, ibuprofen, indomethacin, and related aromatic carboxylic acids for evaluation against SARS-CoV-2 3CL protease enzyme. These ester derivatives were synthesized using EDC in the presence of DMAP to provide various esters in good to excellent yields. Compounds are stable and purified by silica gel chromatography and characterized using 1H-NMR, 13C-NMR, and mass spectral analysis. These synthetic derivatives were evaluated in our in vitro SARS-CoV-2 3CLpro inhibition assay using authentic SARS-CoV-2 3CLpro enzyme. Compounds were also evaluated in our in vitro antiviral assay using quantitative VeroE6 cell-based assay with RNAqPCR. A number of compounds exhibited potent SARS-CoV-2 3CLpro inhibitory activity and antiviral activity. Compound 9a was the most potent inhibitor, with an enzyme IC50 value of 160 nM. Compound 13b exhibited an enzyme IC50 value of 4.9 µM. However, it exhibited a potent antiviral EC50 value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 value of 2.4 µM in the same assay. We assessed the mode of inhibition using mass spectral analysis which suggested the formation of a covalent bond with the enzyme. To obtain molecular insight, we have created a model of compound 9a bound to SARS-CoV-2 3CLpro in the active site. Full article
(This article belongs to the Special Issue Chasing New Therapeutics for COVID-19: Target Identification and Validation, Medicinal Chemistry and Drug Discovery Efforts)
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15 pages, 4586 KiB  
Article
Structural Insight into the Binding of Cyanovirin-N with the Spike Glycoprotein, Mpro and PLpro of SARS-CoV-2: Protein–Protein Interactions, Dynamics Simulations and Free Energy Calculations
by Devashan Naidoo, Pallab Kar, Ayan Roy, Taurai Mutanda, Joseph Bwapwa, Arnab Sen and Akash Anandraj
Molecules 2021, 26(17), 5114; https://doi.org/10.3390/molecules26175114 - 24 Aug 2021
Cited by 12 | Viewed by 2988
Abstract
The emergence of COVID-19 continues to pose severe threats to global public health. The pandemic has infected over 171 million people and claimed more than 3.5 million lives to date. We investigated the binding potential of antiviral cyanobacterial proteins including cyanovirin-N, scytovirin and [...] Read more.
The emergence of COVID-19 continues to pose severe threats to global public health. The pandemic has infected over 171 million people and claimed more than 3.5 million lives to date. We investigated the binding potential of antiviral cyanobacterial proteins including cyanovirin-N, scytovirin and phycocyanin with fundamental proteins involved in attachment and replication of SARS-CoV-2. Cyanovirin-N displayed the highest binding energy scores (−16.8 ± 0.02 kcal/mol, −12.3 ± 0.03 kcal/mol and −13.4 ± 0.02 kcal/mol, respectively) with the spike protein, the main protease (Mpro) and the papainlike protease (PLpro) of SARS-CoV-2. Cyanovirin-N was observed to interact with the crucial residues involved in the attachment of the human ACE2 receptor. Analysis of the binding affinities calculated employing the molecular mechanics-Poisson–Boltzmann surface area (MM-PBSA) approach revealed that all forms of energy, except the polar solvation energy, favourably contributed to the interactions of cyanovirin-N with the viral proteins. With particular emphasis on cyanovirin-N, the current work presents evidence for the potential inhibition of SARS-CoV-2 by cyanobacterial proteins, and offers the opportunity for in vitro and in vivo experiments to deploy the cyanobacterial proteins as valuable therapeutics against COVID-19. Full article
(This article belongs to the Special Issue Chasing New Therapeutics for COVID-19: Target Identification and Validation, Medicinal Chemistry and Drug Discovery Efforts)
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Review

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25 pages, 12063 KiB  
Review
Approaches to the Potential Therapy of COVID-19: A General Overview from the Medicinal Chemistry Perspective
by J. Carlos Menéndez
Molecules 2022, 27(3), 658; https://doi.org/10.3390/molecules27030658 - 20 Jan 2022
Cited by 23 | Viewed by 5567
Abstract
In spite of advances in vaccination, control of the COVID-19 pandemic will require the use of pharmacological treatments against SARS-CoV2. Their development needs to consider the existence of two phases in the disease, namely the viral infection and the inflammatory stages. The main [...] Read more.
In spite of advances in vaccination, control of the COVID-19 pandemic will require the use of pharmacological treatments against SARS-CoV2. Their development needs to consider the existence of two phases in the disease, namely the viral infection and the inflammatory stages. The main targets for antiviral therapeutic intervention are: (a) viral proteins, including the spike (S) protein characteristic of the viral cover and the viral proteases in charge of processing the polyprotein arising from viral genome translation; (b) host proteins, such as those involved in the processes related to viral entry into the host cell and the release of the viral genome inside the cell, the elongation factor eEF1A and importins. The use of antivirals targeted at host proteins is less developed but it has the potential advantage of not being affected by mutations in the genome of the virus and therefore being active against all its variants. Regarding drugs that address the hyperinflammatory phase of the disease triggered by the so-called cytokine storm, the following strategies are particularly relevant: (a) drugs targeting JAK kinases; (b) sphingosine kinase 2 inhibitors; (c) antibodies against interleukin 6 or its receptor; (d) use of the traditional anti-inflammatory corticosteroids. Full article
(This article belongs to the Special Issue Chasing New Therapeutics for COVID-19: Target Identification and Validation, Medicinal Chemistry and Drug Discovery Efforts)
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