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Drug Development and Repositioning Methodology on COVID-19

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A special issue of Current Issues in Molecular Biology (ISSN 1467-3045). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 25378

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Special Issue Editors

Dr. Ki Kwang Oh

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Department of Bio-Health Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Korea
Interests: network pharmacology; drug repurposing; protein–protein interaction; bioinformatics
Special Issues, Collections and Topics in MDPI journals

Dr. Md Adnan

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Guest Editor

Department of Bio-Health Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Republic of Korea
Interests: network pharmacology; system biology; cheminformatics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Currently, a plethora of biomedical information is available concerning COVID-19. In this context, health professionals have been challenged with finding new insights into the mechanisms underlying actions, targets, and drugs.

In particular, “drug-repurposing” is an efficient methodology that generates new therapeutics for approved drugs, but not new chemical compounds. Drug repurposing relies on data-driven approaches, such as bioinformatics, cheminformatics, and system biology, suggesting that integrated network pharmacology can elucidate the signaling pathways (mechanisms), targets, and compounds. These three components could result in a potential candidate to alleviate COVID-19.

In relation to network-based drug repurposing, merged networks also represent a useful tool in the development of COVID-19 drugs.

This Special Issue will focus on current issues in molecular biology from the perspective of computational methods, models based on network pharmacology, and their application to COVID-19.

The submission of original articles, reviews, and hypotheses is welcome. Topics of interest for this issue include, but are not limited to:

The protein–protein interaction networks in COVID-19;
The relationship among signaling-pathways–targets–compounds in COVID-19;
Network pharmacology-based investigation into COVID-19;
COVID-19 and drug treatments, either dry-based or wet-based experiment.

Dr. Ki Kwang Oh
Dr. Md Adnan
Guest Editors

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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. Current Issues in Molecular Biology is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

COVID-19
drug repurposing
bioinformatics
cheminformatics
system biology
network pharmacology

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Published Papers (9 papers)

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24 pages, 9452 KiB

Open AccessArticle

De Novo Design of Anti-COVID Drugs Using Machine Learning-Based Equivariant Diffusion Model Targeting the Spike Protein

by Vidya Niranjan, Akshay Uttarkar, Ananya Ramakrishnan, Anagha Muralidharan, Abhay Shashidhara, Anushri Acharya, Avila Tarani and Jitendra Kumar

Curr. Issues Mol. Biol. 2023, 45(5), 4261-4284; https://doi.org/10.3390/cimb45050271 - 12 May 2023

Cited by 6 | Viewed by 3167

Abstract

The drug discovery and research for an anti-COVID-19 drug has been ongoing despite repurposed drugs in the market. Over time, these drugs were discontinued due to side effects. The search for effective drugs is still under process. The role of Machine Learning (ML) is critical in the search for novel drug compounds. In the current work, using the equivariant diffusion model, we built novel compounds targeting the spike protein of SARS-CoV-2. Using the ML models, 196 de novo compounds were generated which had no hits on any major chemical databases. These novel compounds fulfilled all the criteria of ADMET properties to be lead-like and drug-like compounds. Of the 196 compounds, 15 were docked with high confidence in the target. These compounds were further subjected to molecular docking, the best compound having an IUPAC name of (4aS,4bR,8aS,8bS)-4a,8a-dimethylbiphenylene-1,4,5,8(4aH,4bH,8aH,8bH)-tetraone and a binding score of −6.930 kcal/mol. The principal compound is labeled as CoECG-M1. Density Function Theory (DFT) and Quantum optimization was carried out along with the study of ADMET properties. This suggests that the compound has potential drug-like properties. The docked complex was further subjected to MD simulations, GBSA, and metadynamics simulations to gain insights into the stability of binding. The model can be in the future modified to improve the positive docking rate. Full article

(This article belongs to the Special Issue Drug Development and Repositioning Methodology on COVID-19)

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21 pages, 6442 KiB

Open AccessArticle

Synthesis, Molecular Docking, and Dynamic Simulation Targeting Main Protease (Mpro) of New, Thiazole Clubbed Pyridine Scaffolds as Potential COVID-19 Inhibitors

by Adel Alghamdi, Amr S. Abouzied, Abdulwahab Alamri, Sirajudheen Anwar, Mukhtar Ansari, Ibrahim Khadra, Yasser H. Zaki and Sobhi M. Gomha

Curr. Issues Mol. Biol. 2023, 45(2), 1422-1442; https://doi.org/10.3390/cimb45020093 - 7 Feb 2023

Cited by 35 | Viewed by 3005

Abstract

Many biological activities of pyridine and thiazole derivatives have been reported, including antiviral activity and, more recently, as COVID-19 inhibitors. Thus, in this paper, we designed, synthesized, and characterized a novel series of N-aminothiazole-hydrazineethyl-pyridines, beginning with a N′-(1-(pyridine-3-yl)ethylidene)hydrazinecarbothiohydrazide derivative and various hydrazonoyl chlorides and phenacyl bromides. Their Schiff bases were prepared from the condensation of N-aminothiazole derivatives with 4-methoxybenzaldehyde. FTIR, MS, NMR, and elemental studies were used to identify new products. The binding energy for non-bonding interactions between the ligand (studied compounds) and receptor was determined using molecular docking against the SARS-CoV-2 main protease (PDB code: 6LU7). Finally, the best docked pose with highest binding energy (8a = −8.6 kcal/mol) was selected for further molecular dynamics (MD) simulation studies to verify the outcomes and comprehend the thermodynamic properties of the binding. Through additional in vitro and in vivo research on the newly synthesized chemicals, it is envisaged that the achieved results will represent a significant advancement in the fight against COVID-19. Full article

(This article belongs to the Special Issue Drug Development and Repositioning Methodology on COVID-19)

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17 pages, 2529 KiB

Open AccessArticle

Increased Levels of Autoantibodies against ROS-Modified Proteins in Depressed Individuals with Decrease in Antibodies against SARS-CoV-2 Antigen (S1-RBD)

by Subuhi Sherwani, Mohamed Raafat, Saravanan Rajendrasozhan, Mahvish Khan, Mohd Saleem, Qayyum Husain, Saif Khan, Noor Alam and Mohd Wajid Ali Khan

Curr. Issues Mol. Biol. 2022, 44(11), 5260-5276; https://doi.org/10.3390/cimb44110358 - 28 Oct 2022

Cited by 3 | Viewed by 1890

Abstract

Coronavirus 2019 (COVID-19) disease management is highly dependent on the immune status of the infected individual. An increase in the incidence of depression has been observed during the ongoing COVID-19 pandemic. Autoantibodies against in vitro reactive oxygen species (ROS) modified BSA and Lys as well as antibodies against receptor binding domain subunit S1 (S1-RBD) (S1-RBD-Abs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were estimated using direct binding and competition ELISA. Serum samples were also tested for fasting blood glucose (FBG), malondialdehyde (MDA), carbonyl content (CC), interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Significant structural changes were observed in ROS modified BSA and Lys. Female depressed subjects who were also smokers (F-D-S) showed the highest levels of oxidative stress (MDA and CC levels). Similarly, increased levels of autoantibodies against ROS modified proteins were detected in F-D-S subjects, in males who were depressed and in smokers (M-D-S) compared to the other subjects from the rest of the groups. However, contrary to this observation, levels of S1-RBD-Abs were found to be lowest in the F-D-S and M-D-S groups. During the pandemic, large numbers of individuals have experienced depression, which may induce excessive oxidative stress, causing modifications in circulatory proteins. Thus, the formation of neo-antigens is induced, which lead to the generation of autoantibodies. The concomitant effect of increased autoantibodies with elevated levels of IFN-γ and TNF-α possibly tilt the immune balance toward autoantibody generation rather than the formation of S1-RBD-Abs. Thus, it is important to identify individuals who are at risk of depression to determine immune status and facilitate the better management of COVID-19. Full article

(This article belongs to the Special Issue Drug Development and Repositioning Methodology on COVID-19)

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20 pages, 7031 KiB

Open AccessArticle

Targeting Natural Plant Metabolites for Hunting SARS-CoV-2 Omicron BA.1 Variant Inhibitors: Extraction, Molecular Docking, Molecular Dynamics, and Physicochemical Properties Study

by Heba Ali Hassan, Ahmed R. Hassan, Eslam A. R. Mohamed, Ahmad Al-Khdhairawi, Hala E. Taha, Hanan M. El-Tantawy, Iman A. M. Abdel-Rahman, Ali E. Raslan, Khaled S. Allemailem, Ahmad Almatroudi, Faris Alrumaihi, Maha A. Alshiekheid, Hafiz Muzzammel Rehman, Mahmoud M. Abdelhamid, Islam M. Abdel-Rahman and Ahmed E. Allam

Curr. Issues Mol. Biol. 2022, 44(10), 5028-5047; https://doi.org/10.3390/cimb44100342 - 19 Oct 2022

Cited by 2 | Viewed by 2635

Abstract

(1) Background: SARS-CoV-2 Omicron BA.1 is the most common variation found in most countries and is responsible for 99% of cases in the United States. To overcome this challenge, there is an urgent need to discover effective inhibitors to prevent the emerging BA.1 variant. Natural products, particularly flavonoids, have had widespread success in reducing COVID-19 prevalence. (2) Methods: In the ongoing study, fifteen compounds were annotated from Echium angustifolium and peach (Prunus persica), which were computationally analyzed using various in silico techniques. Molecular docking calculations were performed for the identified phytochemicals to investigate their efficacy. Molecular dynamics (MD) simulations over 200 ns followed by molecular mechanics Poisson–Boltzmann surface area calculations (MM/PBSA) were performed to estimate the binding energy. Bioactivity was also calculated for the best components in terms of drug likeness and drug score. (3) Results: The data obtained from the molecular docking study demonstrated that five compounds exhibited remarkable potency, with docking scores greater than −9.0 kcal/mol. Among them, compounds 1, 2 and 4 showed higher stability within the active site of Omicron BA.1, with ΔG_binding values of −49.02, −48.07, and −67.47 KJ/mol, respectively. These findings imply that the discovered phytoconstituents are promising in the search for anti-Omicron BA.1 drugs and should be investigated in future in vitro and in vivo research. Full article

(This article belongs to the Special Issue Drug Development and Repositioning Methodology on COVID-19)

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17 pages, 3540 KiB

Open AccessArticle

Synthesis and In Silico Study of Some New bis-[1,3,4]thiadiazolimines and bis-Thiazolimines as Potential Inhibitors for SARS-CoV-2 Main Protease

by Sobhi M. Gomha, Sayed M. Riyadh, Magda H. Abdellattif, Tariq Z. Abolibda, Hassan M. Abdel-aziz, AbdElAziz. A. Nayl, Alaa M. Elgohary and Abdo A. Elfiky

Curr. Issues Mol. Biol. 2022, 44(10), 4540-4556; https://doi.org/10.3390/cimb44100311 - 30 Sep 2022

Cited by 7 | Viewed by 2143

Abstract

A novel series of bis-[1,3,4]thiadiazolimines, and bis-thiazolimines, with alkyl linker, were synthesized through general routes from cyclization of 1,1′-(hexane-1,6-diyl)bis(3-phenylthiourea) and hydrazonoyl halides or α-haloketones, respectively. Docking studies were applied to test the binding affinity of the synthesized products against the M^pro of SARS-CoV-2. The best compound, 5h, has average binding energy (−7.50 ± 0.58 kcal/mol) better than that of the positive controls O6K and N3 (−7.36 ± 0.34 and −6.36 ± 0.31 kcal/mol). Additionally, the docking poses (H-bonds and hydrophobic contacts) of the tested compounds against the M^pro using the PLIP web server were analyzed. Full article

(This article belongs to the Special Issue Drug Development and Repositioning Methodology on COVID-19)

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12 pages, 964 KiB

Open AccessArticle

Virtual Screening of Repurposed Drugs as Potential Spike Protein Inhibitors of Different SARS-CoV-2 Variants: Molecular Docking Study

by Ahmad F. Eweas, Hosam-Eldin H. Osman, Ibrahim A. Naguib, Mohammed A. S. Abourehab and Ahmed S. Abdel-Moneim

Curr. Issues Mol. Biol. 2022, 44(7), 3018-3029; https://doi.org/10.3390/cimb44070208 - 4 Jul 2022

Cited by 8 | Viewed by 2706

Abstract

Like most of the RNA viruses, SARS-CoV-2 continuously mutates. Although many mutations have an insignificant impact on the virus properties, mutations in the surface protein, especially those in the receptor-binding domain, may lead to immune or vaccine escape variants, or altered binding activities to both the cell receptor and the drugs targeting such a protein. The current study intended to assess the ability of different variants of interest (VOIs) and variants of concern (VOCs) of SARS-CoV-2 for their affinities of binding to different repurposed drugs. Seven FDA approved drugs, namely, camostat, nafamostat mesylate, fenofibrate, umifenovir, nelfinavir, cefoperazone and ceftazidime, were selected based on their reported in vitro and clinical activities against SARA-CoV-2. The S1 protein subunit from eleven different variants, including the latest highly contiguous omicron variant, were used as targets for the docking study. The docking results revealed that all tested drugs possess moderate to high binding energies to the receptor-binding domain (RBD) of the S1 protein for all different variants. Cefoperazone was found to possess the highest binding energy to the RBD of the S1 protein of all the eleven variants. Ceftazidime was the second-best drug in terms of binding affinity towards the S1 RBD of the investigated variants. On the other hand, fenofibrate showed the least binding affinity towards the RBD of the S1 protein of all eleven variants. The binding affinities of anti-spike drugs varied among different variants. Most of the interacting amino acid residues of the receptor fall within the RBD (438–506). Full article

(This article belongs to the Special Issue Drug Development and Repositioning Methodology on COVID-19)

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22 pages, 3939 KiB

Open AccessArticle

Revealing Potential Bioactive Compounds and Mechanisms of Lithospermum erythrorhizon against COVID-19 via Network Pharmacology Study

by Ki-Kwang Oh and Md. Adnan

Curr. Issues Mol. Biol. 2022, 44(5), 1788-1809; https://doi.org/10.3390/cimb44050123 - 19 Apr 2022

Cited by 2 | Viewed by 2985

Abstract

Lithospermum erythrorhizon (LE) is known in Korean traditional medicine for its potent therapeutic effect and antiviral activity. Currently, coronavirus (COVID-19) disease is a developing global pandemic that can cause pneumonia. A precise study of the infection and molecular pathway of COVID-19 is therefore obviously important. The compounds of LE were identified from the Natural Product Activity and Species Source (NPASS) database and screened by SwissADME. The targets interacted with the compounds and were selected using the Similarity Ensemble Approach (SEA) and Swiss Target Prediction (STP) methods. PubChem was used to classify targets linked to COVID-19. The protein–protein interaction (PPI) networks and signaling pathways–targets–bioactive compounds (STB) networks were constructed by RPackage. Lastly, we performed the molecular docking test (MDT) to verify the binding affinity between significant complexes through AutoDock 1.5.6. The Natural Product Activity and Species Source (NPASS) revealed a total of 82 compounds from LE, which interacted with 1262 targets (SEA and STP), and 249 overlapping targets were identified. The 19 final overlapping targets from the 249 targets and 356 COVID-19 targets were ultimately selected. A bubble chart exhibited that inhibition of the MAPK signaling pathway could be a key mechanism of LE on COVID-19. The three key targets (RELA, TNF, and VEGFA) directly related to the MAPK signaling pathway, and methyl 4-prenyloxycinnamate, tormentic acid, and eugenol were related to each target and had the most stable binding affinity. The three bioactive effects on the three key targets might be synergistic effects to alleviate symptoms of COVID-19 infection. Overall, this study shows that LE can play a role in alleviating COVID-19 symptoms, revealing that the three components (bioactive compounds, targets, and mechanism) are the most significant elements of LE against COVID-19. However, the promising mechanism of LE on COVID-19 is only predicted on the basis of mining data; the efficacy of the chemical compounds and the affinity between compounds and the targets in experiment was ignored, which should be further substantiated through clinical trials. Full article

(This article belongs to the Special Issue Drug Development and Repositioning Methodology on COVID-19)

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Review

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34 pages, 9248 KiB

Open AccessReview

A Clinical Update on SARS-CoV-2: Pathology and Development of Potential Inhibitors

by Desh Deepak Singh, Ihn Han, Eun-Ha Choi and Dharmendra Kumar Yadav

Curr. Issues Mol. Biol. 2023, 45(1), 400-433; https://doi.org/10.3390/cimb45010028 - 4 Jan 2023

Cited by 5 | Viewed by 3107

Abstract

SARS-CoV-2 (severe acute respiratory syndrome) is highly infectious and causes severe acute respiratory distress syndrome (SARD), immune suppression, and multi-organ failure. For SARS-CoV-2, only supportive treatment options are available, such as oxygen supportive therapy, ventilator support, antibiotics for secondary infections, mineral and fluid treatment, and a significant subset of repurposed effective drugs. Viral targeted inhibitors are the most suitable molecules, such as ACE2 (angiotensin-converting enzyme-2) and RBD (receptor-binding domain) protein-based inhibitors, inhibitors of host proteases, inhibitors of viral proteases 3CLpro (3C-like proteinase) and PLpro (papain-like protease), inhibitors of replicative enzymes, inhibitors of viral attachment of SARS-CoV-2 to the ACE2 receptor and TMPRSS2 (transmembrane serine proteinase 2), inhibitors of HR1 (Heptad Repeat 1)–HR2 (Heptad Repeat 2) interaction at the S2 protein of the coronavirus, etc. Targeting the cathepsin L proteinase, peptide analogues, monoclonal antibodies, and protein chimaeras as RBD inhibitors interferes with the spike protein’s ability to fuse to the membrane. Targeting the cathepsin L proteinase, peptide analogues, monoclonal antibodies, and protein chimaeras as RBD inhibitors interferes with the spike protein’s ability to fuse to the membrane. Even with the tremendous progress made, creating effective drugs remains difficult. To develop COVID-19 treatment alternatives, clinical studies are examining a variety of therapy categories, including antibodies, antivirals, cell-based therapy, repurposed diagnostic medicines, and more. In this article, we discuss recent clinical updates on SARS-CoV-2 infection, clinical characteristics, diagnosis, immunopathology, the new emergence of variant, SARS-CoV-2, various approaches to drug development and treatment options. The development of therapies has been complicated by the global occurrence of many SARS-CoV-2 mutations. Discussion of this manuscript will provide new insight into drug pathophysiology and drug development. Full article

(This article belongs to the Special Issue Drug Development and Repositioning Methodology on COVID-19)

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25 pages, 5773 KiB

Open AccessReview

Review of Developments in Combating COVID-19 by Vaccines, Inhibitors, Radiations, and Nonthermal Plasma

by Ihn Han, Sohail Mumtaz, Sekar Ashokkumar, Dharmendra Kumar Yadav and Eun Ha Choi

Curr. Issues Mol. Biol. 2022, 44(11), 5666-5690; https://doi.org/10.3390/cimb44110384 - 15 Nov 2022

Cited by 6 | Viewed by 2620

Abstract

Global society has been highly pressured by the COVID-19 pandemic, which has exposed vulnerabilities in supply chains for disinfection products, personal protective equipment, and medical resources worldwide. It is critically necessary to find effective treatments and medications for these viral infections. This review summarizes and emphasizes critical features of recent breakthroughs in vaccines, inhibitors, radiations, and innovative nonthermal atmospheric plasma (NTAP) technologies to inactivate COVID-19. NTAP has emerged as an effective, efficient, and safe method of viral inactivation. NTAP can be used to inactivate viruses in an environmentally friendly manner, as well as activate animal and plant viruses in a variety of matrices. Researchers and engineers desire to help the medical world deal with the ongoing COVID-19 epidemic by establishing techniques that make use of widely available NTAP technologies. NTAP technology is not dependent on viral strain, and it does not necessitate months or years of research to develop specific vaccines for each novel or arising viral disease. We believe the NTAP is a highly promising technique for combating COVID-19 and other viruses. Thus, NTAP technology could be a significant breakthrough in the near future in assisting humans in combating COVID-19 infections. We hope that this review provides a platform for readers to examine the progress made in the fight against COVID-19 through the use of vaccines, inhibitors, radiation, and NTAP. Full article

(This article belongs to the Special Issue Drug Development and Repositioning Methodology on COVID-19)

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