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Drug Design and Discovery for Treatment of Coronavirus Disease (COVID-19)

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 18552

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Special Issue Editor

Dr. Ross Larue

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Guest Editor

Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USA
Interests: retroviruses; HIV-1; protein–protein interactions; Brd4-mediated cancers; drug discovery; small-molecule inhibitors; antivirals
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue, “Drug Design and Discovery for Treatment of Coronavirus Disease-19 (Covid-19)” is related to the ongoing Covid-19 pandemic and will focus on the current advances and challenges in discovering and developing effective drugs targeting severe acute respiratory syndrome coronavirus (SARS-CoV)-2.

SARS-CoV-2 is a novel and highly pathogenic coronavirus and is the causative agent of the coronavirus disease 2019 (COVID-19). While many advances have been made in developing vaccines, there is still a critical need for developing effective antiviral therapies. Avenues for developing SARS-CoV-2 therapies could include inhibitors that target essential viral proteins, high throughput screening campaigns targeting viral replication, novel therapies regulating the host immune system, or the repurposing of existing drugs among many other approaches. Such endeavors and discoveries will complement ongoing vaccination rollouts and will remain at the forefront as we combat this global pandemic.

All researchers working in the fields of drug discovery and improvement, viral inhibition, and pre-clinical studies with novel therapies are cordially invited to contribute original research papers or reviews to this Special Issue of Molecules, which report on efforts towards targeting SARS-CoV-2.

Dr. Ross Larue
Guest Editor

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

Covid-19
drug discovery
SARS-CoV-2
coronavirus targeting drugs
repurposing viral inhibitors
drug screening
rational drug design

Published Papers (6 papers)

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Research

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22 pages, 11167 KiB

Open AccessArticle

Identification and Inhibition of the Druggable Allosteric Site of SARS-CoV-2 NSP10/NSP16 Methyltransferase through Computational Approaches

by Shah Faisal, Syed Lal Badshah, Bibi Kubra, Mohamed Sharaf, Abdul-Hamid Emwas, Mariusz Jaremko and Mohnad Abdalla

Molecules 2022, 27(16), 5241; https://doi.org/10.3390/molecules27165241 - 17 Aug 2022

Cited by 10 | Viewed by 2418

Abstract

Since its emergence in early 2019, the respiratory infectious virus, SARS-CoV-2, has ravaged the health of millions of people globally and has affected almost every sphere of life. Many efforts are being made to combat the COVID-19 pandemic’s emerging and recurrent waves caused by its evolving and more infectious variants. As a result, novel and unexpected targets for SARS-CoV-2 have been considered for drug discovery. 2′-O-Methyltransferase (nsp10/nsp16) is a significant and appealing target in the SARS-CoV-2 life cycle because it protects viral RNA from the host degradative enzymes via a cap formation process. In this work, we propose prospective allosteric inhibitors that target the allosteric site, SARS-CoV-2 MTase. Four drug libraries containing ~119,483 compounds were screened against the allosteric site of SARS-CoV-2 MTase identified in our research. The identified best compounds exhibited robust molecular interactions and alloscore-score rankings with the allosteric site of SARS-CoV-2 MTase. Moreover, to further assess the dynamic stability of these compounds (CHEMBL2229121, ZINC000009464451, SPECS AK-91811684151, NCI-ID = 715319), a 100 ns molecular dynamics simulation, along with its holo-form, was performed to provide insights on the dynamic nature of these allosteric inhibitors at the allosteric site of the SARS-CoV-2 MTase. Additionally, investigations of MM-GBSA binding free energies revealed a good perspective for these allosteric inhibitor–enzyme complexes, indicating their robust antagonistic action on SARS-CoV-2 (nsp10/nsp16) methyltransferase. We conclude that these allosteric repressive agents should be further evaluated through investigational assessments in order to combat the proliferation of SARS-CoV-2. Full article

(This article belongs to the Special Issue Drug Design and Discovery for Treatment of Coronavirus Disease (COVID-19))

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13 pages, 1644 KiB

Open AccessArticle

Bioavailability Enhancement of Cepharanthine via Pulmonary Administration in Rats and Its Therapeutic Potential for Pulmonary Fibrosis Associated with COVID-19 Infection

by Jian Li, Guangrui Chen, Zhiyun Meng, Zhuona Wu, Hui Gan, Xiaoxia Zhu, Peng Han, Taoyun Liu, Fanjun Wang, Ruolan Gu and Guifang Dou

Molecules 2022, 27(9), 2745; https://doi.org/10.3390/molecules27092745 - 24 Apr 2022

Cited by 6 | Viewed by 2785

Abstract

Cepharanthine (CEP) has excellent anti-SARS-CoV-2 properties, indicating its favorable potential for COVID-19 treatment. However, its application is challenged by its poor dissolubility and oral bioavailability. The present study aimed to improve the bioavailability of CEP by optimizing its solubility and through a pulmonary delivery method, which improved its bioavailability by five times when compared to that through the oral delivery method (68.07% vs. 13.15%). An ultra-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS) method for quantification of CEP in rat plasma was developed and validated to support the bioavailability and pharmacokinetic studies. In addition, pulmonary fibrosis was recognized as a sequela of COVID-19 infection, warranting further evaluation of the therapeutic potential of CEP on a rat lung fibrosis model. The antifibrotic effect was assessed by analysis of lung index and histopathological examination, detection of transforming growth factor (TGF)-β1, interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), and hydroxyproline level in serum or lung tissues. Our data demonstrated that CEP could significantly alleviate bleomycin (BLM)-induced collagen accumulation and inflammation, thereby exerting protective effects against pulmonary fibrosis. Our results provide evidence supporting the hypothesis that pulmonary delivery CEP may be a promising therapy for pulmonary fibrosis associated with COVID-19 infection. Full article

(This article belongs to the Special Issue Drug Design and Discovery for Treatment of Coronavirus Disease (COVID-19))

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13 pages, 3114 KiB

Open AccessArticle

Computational Screening of Phenylamino-Phenoxy-Quinoline Derivatives against the Main Protease of SARS-CoV-2 Using Molecular Docking and the ONIOM Method

by Suwicha Patnin, Arthit Makarasen, Pongsit Vijitphan, Apisara Baicharoen, Apinya Chaivisuthangkura, Mayuso Kuno and Supanna Techasakul

Molecules 2022, 27(6), 1793; https://doi.org/10.3390/molecules27061793 - 09 Mar 2022

Cited by 8 | Viewed by 2867

Abstract

In the search for new anti-HIV-1 agents, two forms of phenylamino-phenoxy-quinoline derivatives have been synthesized, namely, 2-phenylamino-4-phenoxy-quinoline and 6-phenylamino-4-phenoxy-quinoline. In this study, the binding interactions of phenylamino-phenoxy-quinoline derivatives and six commercially available drugs (hydroxychloroquine, ritonavir, remdesivir, S-217622, N3, and PF-07321332) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M^pro) were investigated using molecular docking and the ONIOM method. The molecular docking showed the hydrogen bonding and hydrophobic interactions of all the compounds in the pocket of SARS-CoV-2 main protease (M^pro), which plays an important role for the division and proliferation of the virus into the cell. The binding free energy values between the ligands and M^pro ranged from −7.06 to −10.61 kcal/mol. The molecular docking and ONIOM results suggested that 4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline and 4-(4′-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline have low binding energy values and appropriate molecular properties; moreover, both compounds could bind to M^pro via hydrogen bonding and Pi-Pi stacking interactions with amino acid residues, namely, HIS41, GLU166, and GLN192. These amino acids are related to the proteolytic cleavage process of the catalytic triad mechanisms. Therefore, this study provides important information for further studies on synthetic quinoline derivatives as antiviral candidates in the treatment of SARS-CoV-2. Full article

(This article belongs to the Special Issue Drug Design and Discovery for Treatment of Coronavirus Disease (COVID-19))

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28 pages, 27910 KiB

Open AccessArticle

Marine Brominated Tyrosine Alkaloids as Promising Inhibitors of SARS-CoV-2

by Amr El-Demerdash, Afnan Hassan, Tarek Mohamed Abd El-Aziz, James D. Stockand and Reem K. Arafa

Molecules 2021, 26(20), 6171; https://doi.org/10.3390/molecules26206171 - 13 Oct 2021

Cited by 8 | Viewed by 2194

Abstract

There have been more than 150 million confirmed cases of SARS-CoV-2 since the beginning of the pandemic in 2019. By June 2021, the mortality from such infections approached 3.9 million people. Despite the availability of a number of vaccines which provide protection against this virus, the evolution of new viral variants, inconsistent availability of the vaccine around the world, and vaccine hesitancy, in some countries, makes it unreasonable to rely on mass vaccination alone to combat this pandemic. Consequently, much effort is directed to identifying potential antiviral treatments. Marine brominated tyrosine alkaloids are recognized to have antiviral potential. We test here the antiviral capacity of fourteen marine brominated tyrosine alkaloids against five different target proteins from SARS-CoV-2, including main protease (M^pro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and non-structural protein 10 (nsp10) (PDB ID: 6W4H). These marine alkaloids, particularly the hexabrominated compound, fistularin-3, shows promising docking interactions with predicted binding affinities (S-score = −7.78, −7.65, −6.39, −6.28, −8.84 Kcal/mol) for the main protease (M^pro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and non-structural protein 10 (nsp10) (PDB ID: 6W4H), respectively, where it forms better interactions with the protein pockets than the native interaction. It also shows promising molecular dynamics, pharmacokinetics, and toxicity profiles. As such, further exploration of the antiviral properties of fistularin-3 against SARS-CoV-2 is merited. Full article

(This article belongs to the Special Issue Drug Design and Discovery for Treatment of Coronavirus Disease (COVID-19))

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12 pages, 1986 KiB

Open AccessArticle

Receptor-Based Pharmacophore Modeling in the Search for Natural Products for COVID-19 M^pro

by Mohd Saeed, Amir Saeed, Md Jahoor Alam and Mousa Alreshidi

Molecules 2021, 26(6), 1549; https://doi.org/10.3390/molecules26061549 - 11 Mar 2021

Cited by 15 | Viewed by 3485

Abstract

Considering the urgency of the COVID-19 pandemic, we developed a receptor-based pharmacophore model for identifying FDA-approved drugs and hits from natural products. The COVID-19 main protease (M^pro) was selected for the development of the pharmacophore model. The model consisted of a hydrogen bond acceptor, donor, and hydrophobic features. These features demonstrated good corroboration with a previously reported model that was used to validate the present model, showing an RMSD value of 0.32. The virtual screening was carried out using the ZINC database. A set of 208,000 hits was extracted and filtered using the ligand pharmacophore mapping, applying the lead-like properties. Lipinski’s filter and the fit value filter were used to minimize hits to the top 2000. Simultaneous docking was carried out for 200 hits for natural drugs belonging to the FDA-approved drug database. The top 28 hits from these experiments, with promising predicted pharmacodynamic and pharmacokinetic properties, are reported here. To optimize these hits as M^pro inhibitors and potential treatment options for COVID-19, bench work investigations are needed. Full article

(This article belongs to the Special Issue Drug Design and Discovery for Treatment of Coronavirus Disease (COVID-19))

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Other

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20 pages, 699 KiB

Open AccessPerspective

Drug Repurposing for COVID-19: A Review and a Novel Strategy to Identify New Targets and Potential Drug Candidates

by Liliana Rodrigues, Renata Bento Cunha, Tatiana Vassilevskaia, Miguel Viveiros and Celso Cunha

Molecules 2022, 27(9), 2723; https://doi.org/10.3390/molecules27092723 - 23 Apr 2022

Cited by 29 | Viewed by 3468

Abstract

In December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) was first identified in the province of Wuhan, China. Since then, there have been over 400 million confirmed cases and 5.8 million deaths by COVID-19 reported worldwide. The urgent need for therapies against SARS-CoV-2 led researchers to use drug repurposing approaches. This strategy allows the reduction in risks, time, and costs associated with drug development. In many cases, a repurposed drug can enter directly to preclinical testing and clinical trials, thus accelerating the whole drug discovery process. In this work, we will give a general overview of the main developments in COVID-19 treatment, focusing on the contribution of the drug repurposing paradigm to find effective drugs against this disease. Finally, we will present our findings using a new drug repurposing strategy that identified 11 compounds that may be potentially effective against COVID-19. To our knowledge, seven of these drugs have never been tested against SARS-CoV-2 and are potential candidates for in vitro and in vivo studies to evaluate their effectiveness in COVID-19 treatment. Full article

(This article belongs to the Special Issue Drug Design and Discovery for Treatment of Coronavirus Disease (COVID-19))

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