Curcumins and its derivatives as potential inhibitors of New Coronavirus (COVID-19) main protease: an in silico strategy

Coronavirus (COVID-19) disease outbreak caused a worldwide pandemic with a powerful lethal potential and still, there is no specific treatment to it. Natural bioactive molecules like curcumins were investigated in this work aiming to block the active site of COVID-19 Main protease (Mpro), since they present several biological activities, being more suitable in terms of fewer side effects, once this disease overloads the immune system of patients. Hereby, curcumin and several derivatives were screened for their ability to react with Mpro receptors (PDB: 6LU7). N3, Azithromycin (AZT), and Baracitinib (BRT) were evaluated as positive controls and in combined therapeutics possibilities with curcumins. N3, AZT, and BRT bound to different protein receptors, and also it was observed that N3 bound in the same site as hexahydrocurcumin and curcumin glucuronide bound at the AZT’s site and bisdemethoxycurcumin, curcumin, curcumin sulfate, cyclocurcumin, demethoxycurcumin, dihydrocurcumin and hexahydrocurcuminol bound at BRT’s site. All molecules analyzed have high force interaction fields. Once the viral activity is mainly intracellular, these compounds also were evaluated for their hydropathic abilities. All molecules were classified and considered capable of membrane cell invading. These results suggest that the therapeutic approach of the curcumin derivatives associated with AZT and the antiviral inhibitor N3 is promissory for future evaluation of their synergism in in vitro and in vivo tests to define their additional viability in the treatment of COVID-19.

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Phytochemicals of Rhus spp. as Potential Inhibitors of the SARS-CoV-2 Main Protease: Molecular Docking and Drug-Likeness Study

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/8814890 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Yousery E. Sherif ◽

Sami A. Gabr ◽

Nasser M. Hosny ◽

Ahmad H. Alghadir ◽

Rayan Alansari

Keyword(s):

Molecular Docking ◽

Specific Treatment ◽

Polyphenolic Compounds ◽

Protease Enzyme ◽

Main Protease ◽

Synthetic Accessibility ◽

Novel Coronavirus ◽

Potential Inhibitors

Background. The outbreak of coronavirus disease 2019 (COVID-19) induced by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated in China and spread to cover the entire world with an ongoing pandemic. The magnitude of the situation and the fast spread of the new and deadly virus, as well as the lack of specific treatment, led to a focus on research to discover new therapeutic agents. Aim. In this study, we explore the potential inhibitory effects of some active polyphenolic constituents of Rhus spp. (sumac) against the SARS-CoV-2 main protease enzyme (Mpro; 6LU7). Methods. 26 active polyphenolic compounds of Rhus spp. were studied for their antiviral activity by molecular docking, drug likeness, and synthetic accessibility score (SAS) as inhibitors against the SARS-CoV-2 Mpro. Results. The results show that all tested compounds of sumac provided good interaction with the main active site of SARS-CoV-2 Mpro, with better, lower molecular docking energy (kcal/mol) compared to the well-known drugs chloroquine and favipiravir (Avigan). Only six active polyphenolic compounds of Rhus spp. (sumac), methyl 3,4,5-trihydroxybenzoate, (Z)-1-(2,4-dihydroxyphenyl)-3-(3,4-dihydroxyphenyl)-2-hydroxyprop-2-en-1-one, (Z)-2-(3,4-dihydroxybenzylidene)-6-hydroxybenzofuran-3(2H)-one, 3,5,7-trihydroxy-2-(4-hydroxyphenyl)chroman-4-one, 2-(3,4-dihydroxyphenyl)-3,5-dihydroxy-7-methoxy-4H-chroman-4-one, and 3,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one, were proposed by drug likeness, solubility in water, and SAS analysis as potential inhibitors of Mpro that may be used for the treatment of COVID-19. Conclusion. Six phenolic compounds of Rhus spp. are proposed for synthesis as potential inhibitors against Mpro and have potential for the treatment of COVID-19. These results encourage further in vitro and in vivo investigations of the proposed ligands and research on the preventive use of Rhus spp. against SARS-CoV-2.

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A Potential Peptide From Soy Cheese Produced Using Lactobacillus delbrueckii WS4 for Effective Inhibition of SARS-CoV-2 Main Protease and S1 Glycoprotein

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.601753 ◽

2020 ◽

Vol 7 ◽

Author(s):

Rounak Chourasia ◽

Srichandan Padhi ◽

Loreni Chiring Phukon ◽

Md Minhajul Abedin ◽

Sudhir P. Singh ◽

...

Keyword(s):

Drug Targets ◽

Docking Studies ◽

Lactobacillus Delbrueckii ◽

Amino Acid Residues ◽

Main Protease ◽

Effective Inhibition ◽

Cheese Peptides ◽

Potential Inhibitors

The COVID-19 pandemic caused by novel SARS-CoV-2 has resulted in an unprecedented loss of lives and economy around the world. In this study, search for potential inhibitors against two of the best characterized SARS-CoV-2 drug targets: S1 glycoprotein receptor-binding domain (RBD) and main protease (3CLPro), was carried out using the soy cheese peptides. A total of 1,420 peptides identified from the cheese peptidome produced using Lactobacillus delbrueckii WS4 were screened for antiviral activity by employing the web tools, AVPpred, and meta-iAVP. Molecular docking studies of the selected peptides revealed one potential peptide “KFVPKQPNMIL” that demonstrated strong affinity toward significant amino acid residues responsible for the host cell entry (RBD) and multiplication (3CLpro) of SARS-CoV-2. The peptide was also assessed for its ability to interact with the critical residues of S1 RBD and 3CLpro of other β-coronaviruses. High binding affinity was observed toward critical amino acids of both the targeted proteins in SARS-CoV, MERS-CoV, and HCoV-HKU1. The binding energy of KFVPKQPNMIL against RBD and 3CLpro of the four viruses ranged from −8.45 to −26.8 kcal/mol and −15.22 to −22.85 kcal/mol, respectively. The findings conclude that cheese, produced by using Lb. delbrueckii WS4, could be explored as a prophylactic food for SARS-CoV-2 and related viruses. In addition, the multi-target inhibitor peptide, which effectively inhibited both the viral proteins, could further be used as a terminus a quo for the in vitro and in vivo function against SARS-CoV-2.

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In vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of novel semisynthetic analogues

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01995-20 ◽

2020 ◽

Author(s):

Fidelia Ijeoma Uche ◽

Xiaozhen Guo ◽

Jude Okokon ◽

Imran Ullah ◽

Paul Horrocks ◽

...

Keyword(s):

Metabolic Pathways ◽

High Performance ◽

Antimalarial Activity ◽

Biological Activities ◽

Antiplasmodial Activity ◽

Survival Times ◽

Antiproliferative Effects ◽

Future Evaluation

Bisbenzylisoquinoline (BBIQ) alkaloids are a diverse group of natural products that demonstrate a range of biological activities. In this study, the in vitro antiplasmodial activity of three BBIQ alkaloids (cycleanine (1), isochondodendrine (2) and 2′-norcocsuline (3)) isolated from the Triclisia subcordata Oliv. medicinal plant traditionally used for the treatment of malaria in Nigeria are studied alongside two semi-synthetic analogues (4 and 5) of cycleanine. The antiproliferative effects against a chloroquine-resistant Plasmodium falciparum strain were determined using a SYBR Green 1 fluorescence assay. The in vivo antimalarial activity of cycleanine (1) is then investigated in suppressive, prophylactic and curative murine malaria models after infection with a chloroquine-sensitive Plasmodium berghei strain. BBIQ alkaloids (1–5) exerted in vitro antiplasmodial activities with IC50 at low micromolar concentrations with the two semi-synthetic cycleanine analogues showing an improved potency and selectivity than cycleanine. At oral doses of 25 and 50mg/kg body weight of infected mice, cycleanine suppressed the levels of parasitaemia, and increased mean survival times significantly compared to the control groups. The metabolites and metabolic pathways of cycleanine (1) were also studied using high performance liquid chromatography electrospray ionization tandem mass spectrometry. Twelve novel metabolites were detected in rats after intragastic administration of cycleanine. The metabolic pathways of cycleanine were demonstrated to involve hydroxylation, dehydrogenation, and demethylation. Overall, these in vitro and in vivo results provide a basis for the future evaluation of cycleanine and its analogues as leads for further development.

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Virtual Screening of Potential Inhibitors for SARS-CoV-2 Main Protease

10.20944/preprints202004.0146.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Carlos Javier Alméciga-Díaz ◽

Luisa N. Pimentel-Vera ◽

Angela Caro ◽

Angela Mosquera ◽

Camilo Andrés Castellanos Moreno ◽

...

Keyword(s):

Virtual Screening ◽

Clinical Information ◽

Virus Genome ◽

Pharmacological Agents ◽

Main Protease ◽

Novel Coronavirus ◽

Approved Drugs ◽

Potential Inhibitors

Coronavirus Disease 2019 (Covid-19) was first described in December 2019 in Wuhan, Hubei Province, China; and produced by a novel coronavirus designed as the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Covid-19 has become a pandemic reaching over 1.3 million confirmed cases and 73,000 deaths. Several efforts have been done to identify pharmacological agents that can be used to treat patients and protect healthcare professionals. The sequencing of the virus genome not only has offered the possibility to develop a vaccine, but also to identified and characterize the virus proteins. Among these proteins, main protease (Mpro) has been identified as a potential therapeutic target, since it is essential for the processing other viral proteins. Crystal structures of SARS-CoV-2 Mpro and inhibitors has been described during the last months. To describe additional compounds that can inhibit SARS-CoV-2 Mpro, in this study we performed a molecular docking-based virtual screening against a library of experimental and approved drugs. Top 10 hits included Pictilisib, Nimorazole, Ergoloid mesylates, Lumacaftor, Cefuroxime, Cepharanhine, and Nilotinib. These compounds were predicted to have higher binding affinity for SARS-CoV-2 Mpro than previously reported inhibitors for this protein, suggesting a higher potential to inhibit virus replication. Since the identified drugs have both pre-clinical and clinical information, we consider that these results may contribute to the identification of treatment alternative for Covid-19. Nevertheless, in vitro and in vivo confirmation should be performed before these compounds could be translated to the clinic.

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Protein Hydrolysates from Anchovy (Engraulis encrasicolus) Waste: In Vitro and In Vivo Biological Activities

Marine Drugs ◽

10.3390/md18020086 ◽

2020 ◽

Vol 18 (2) ◽

pp. 86 ◽

Cited By ~ 4

Author(s):

Alessia Giannetto ◽

Emanuela Esposito ◽

Marika Lanza ◽

Sabrina Oliva ◽

Kristian Riolo ◽

...

Keyword(s):

Oxidative Stress ◽

Biological Activities ◽

Protein Hydrolysates ◽

Bioactive Molecules ◽

Nutritional Properties ◽

Fish Waste ◽

In Vivo Models ◽

Engraulis Encrasicolus

Fish waste utilization to obtain protein hydrolysates has been demonstrated to be a useful strategy to face both environmental and economic impacts while obtaining high-value products with remarkable biological and nutritional properties. In the present study, protein hydrolysates obtained from anchovy Engraulis encrasicolus (APH) by-products were assessed for their potential biological activities in both in vitro and in vivo models. The treatment with APH exerted a significant protection against LPS-induced inflammation in RAW 264.7 cells, decreasing the protein expression of pro-inflammatory mediators (i.e., COX-2) and inhibiting the nuclear translocation of NF-κB through IκB-α. Moreover, APH modulated the expression of iNOS, MnSOD and HO-1, thus decreasing the severity of oxidative stress. The supplementation of APH in the diet of ApoE knockout mice down-regulated the proinflammatory cytokines (i.e., TNF-α, IL-1α, IL-1β, IL-6) in both aorta and heart tissues, and modulated the expression of oxidative stress-related genes (Cu/ZnSod, MnSod, Cat, Gpx and Ho), indicating that APH can exert a beneficial role, having anti-inflammatory and antioxidant activities. The nutritional properties of APH, together with their biological activities herein reported, highlight the possibility of obtaining bioactive molecules from fish waste and encourage their use as potential nutraceuticals in food and pharmaceutical industries in the next future.

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In Silico Screening of Naturally Occurring Coumarin Derivatives for the Inhibition of the Main Protease of SARS-CoV-2

10.26434/chemrxiv.12234728 ◽

2020 ◽

Author(s):

Sona Lyndem ◽

Sharat Sarmah ◽

Sourav Das ◽

Atanu Singha Roy

Keyword(s):

Active Site ◽

Preliminary Screening ◽

Naturally Occurring ◽

Main Protease ◽

Coumarin Compounds ◽

Potential Inhibitors ◽

Novel Drug ◽

Catalytic Dyad

The dissemination of a novel corona virus, SARS-CoV-2, through rapid human to human transmission has led to a global health emergency. The lack of a vaccine or medication for effective treatment of this disease has made it imperative for developing novel drug discovery approaches. Repurposing of drugs is one such method currently being used to tackle the viral infection. The genome of SARS-CoV-2 replicates due to the functioning of a main protease called Mpro. By targeting the active site of Mpro with potential inhibitors, this could prevent viral replication from taking place. Blind docking technique was used to investigate the interactions between 29 naturally occurring coumarin compounds and SARS-CoV-2 main protease, Mpro, out of which 17 coumarin compounds were seen to bind to the active site through the interaction with the catalytic dyad, His41 and Cys145, along with other neighbouring residues. On comparing the ΔG values of the coumarins bound to the active site of Mpro, corymbocoumarin belonging to the class pyranocoumarins, methylgalbanate belonging to the class simple coumarins and heraclenol belonging to the class furanocoumarins, displayed best binding efficiency and could be considered as potential Mpro protease inhibitors. Preliminary screening of these naturally occurring coumarin compounds as potential SARS-CoV-2 replication inhibitors acts as a stepping stone for further in vitro and in vivo experimental investigation and analytical validation.

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Thespesia populnea: An Ethnomedicinal, Phytochemical and Pharmacological review

The Natural Products Journal ◽

10.2174/2210315510999201210142313 ◽

2020 ◽

Vol 10 ◽

Author(s):

Ashish Vishwakarma ◽

Poonam Arora ◽

Mahaveer Dhobi

Keyword(s):

Therapeutic Potential ◽

Biological Activities ◽

Experimental Studies ◽

Bioactive Molecules ◽

Chemical Components ◽

Coastal Forests ◽

Thespesia Populnea ◽

Wide Range

: Thespesia populnea, family, Malvaceae, commonly known as paras pipal and Indian tulip tree, is widely distributed in coastal forests of India and south-eastern areas. The plant is medicinally used for the treatment of numerous diseases including cutaneous infections, brain and liver disorders.The review summarizes all the information related to botanical characteristics, traditional uses, chemical components and biological activities of T. populnea, in order to exploit therapeutic potential of this plant.x.The available information about T. populnea was collected through the online search on Web of Science, PubMed, Science Direct, Springer and Google Scholar. T. populnea is widely explored concerning its phytochemistry and biological activities. Amongst all phytoconstituents present in Thespesia, sesquiterpenes and phenolic compounds are major bioactive ingredients in plant. Experimental studies show that these compounds exhibit a wide range of biological activities including anti-inflammatory, antidiabetic, analgesic, wound healing, anti-alzheimer, anti-ulcer and anti-psoriasis in in vitro and in vivo animal studies.To sum up, the plant, T. populnea, possess high medicinal and social value, that deserves further investigation. T. populnea is promising plant to be utilized in the development of pharmaceutical drug products. However, there is a lack of scientific studies to confirm its ethnopharmcological uses. In addition, further studies on isolation of bioactive molecules and their pharmacological studies are recommended that could be of great significance towards clinical application of this plant.

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Bee Venom: An Updating Review of Its Bioactive Molecules and Its Health Applications

Nutrients ◽

10.3390/nu12113360 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3360

Author(s):

Maria Carpena ◽

Bernabe Nuñez-Estevez ◽

Anton Soria-Lopez ◽

Jesus Simal-Gandara

Keyword(s):

Therapeutic Potential ◽

Biological Activities ◽

Bee Venom ◽

Bioactive Molecules ◽

Antitumor Effects ◽

Ancient Medicine ◽

Health Applications ◽

Proteins And Peptides

Bee venom (BV) is usually associated with pain since, when humans are stung by bees, local inflammation and even an allergic reaction can be produced. BV has been traditionally used in ancient medicine and in acupuncture. It consists of a mixture of substances, principally of proteins and peptides, including enzymes as well as other types of molecules in a very low concentration. Melittin and phospholipase A2 (PLA2) are the most abundant and studied compounds of BV. Literature of the main biological activities exerted by BV shows that most studies focuses on the comprehension and test of anti-inflammatory effects and its mechanisms of action. Other properties such as antioxidant, antimicrobial, neuroprotective or antitumor effects have also been assessed, both in vitro and in vivo. Moreover, human trials are necessary to confirm those clinical applications. However, notwithstanding the therapeutic potential of BV, there are certain problems regarding its safety and the possible appearance of adverse effects. On this perspective, new approaches have been developed to avoid these complications. This manuscript is aimed at reviewing the actual knowledge on BV components and its associated biological activities as well as the latest advances on this subject.

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Hydrogel-Based Scaffolds in Oral Tissue Engineering

Frontiers in Materials ◽

10.3389/fmats.2021.708945 ◽

2021 ◽

Vol 8 ◽

Author(s):

Alfredo Ayala-Ham ◽

Jorge López-Gutierrez ◽

Mercedes Bermúdez ◽

Maribel Aguilar-Medina ◽

Juan Ignacio Sarmiento-Sánchez ◽

...

Keyword(s):

Tissue Engineering ◽

Biological Activities ◽

Biological Effects ◽

Bioactive Molecules ◽

Gingival Tissue ◽

High Water Content ◽

Cellular Processes ◽

Periodontal Tissues

Regenerative therapy in dentistry has gained interest given the complexity to restore dental and periodontal tissues with inert materials. The best approach for regeneration requires three elements for restoring functions of affected or diseased organ tissues: cells, bioactive molecules, and scaffolds. This triad is capable of modulating the processes to replace lost or damaged tissues and restore function, as it has an impact on diverse cellular processes, influencing cell behavior positively to induce the complete restoration of function and morphology of such complex tissues. Hydrogels (HG) have shown advantages as scaffolds as they are soft and elastic three-dimensional (3D) networks formed from hydrophilic homopolymers, copolymers, or macromers. Besides simple or hybrid, HG show chemical, mechanical and biological activities such as the incorporation of cells in their structures, the retention of high-water content which enhances the transportation of cell nutrients and waste, and elastic and flexible characteristics that emulate the native extracellular matrix (ECM). HG can induce changes in cellular processes such as chemotaxis, proliferation, angiogenesis, biomineralization, and expression of specific tissue biomarkers, enhancing the regeneration process. Besides some of them have anti-inflammatory and anti-bacterial effects. This review aims to show an extensive overview of the most used hydrogels in tissue engineering, emphasizing those that are studied for the regeneration of oral tissues, their biological effects, and their clinical implications. Even though most of the HG are still under investigation, some of them have been studied in vitro and in vivo with outstanding results that may lead to preclinical studies. Besides there are HG that have shown their efficacy in patients such as hyaluronan HG that enhances the healing of gingival tissue.

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Drug Leads Derived from Japanese Marine Organisms

Current Medicinal Chemistry ◽

10.2174/0929867326666191022125851 ◽

2020 ◽

Vol 28 (1) ◽

pp. 196-210 ◽

Cited By ~ 1

Author(s):

Daisuke Uemura ◽

Yoshinori Kawazoe ◽

Toshiyasu Inuzuka ◽

Yuki Itakura ◽

Chiari Kawamata ◽

...

Keyword(s):

Natural Products ◽

Biological Activities ◽

Marine Organisms ◽

Bioactive Molecules ◽

Major Work ◽

Halichondrin B ◽

Chemical Structures ◽

Biological Phenomena

: Many natural products with extraordinary chemical structures and brilliant biological activities have been obtained from marine organisms. We have investigated such fascinating bioactive molecules, exemplified by the potent marine toxin palytoxin and the antitumor molecule halichondrin B, which has been developed as the anticancer drug Halaven®, to explore novel frontiers in organic chemistry and bioscience. Working within the traditional discipline, we have sought to acquire a deeper understanding of biological phenomena. We introduce here our major work along with up-todate topics. We isolated yoshinone A from marine cyanobacteria and completed a gram-scale synthesis. Yoshinone A is a novel polyketide that inhibited the differentiation of 3T3-L1 cells into adipocytes without significant cytotoxicity. The detailed mechanisms of action will be elucidated via further experiments in vitro and in vivo. In this study, we explore the true producers of okadaic acid and halichondrin B by immunostaining of Halichondria okadai with an antibody that was prepared using these natural products as an antigen. We will analyze isolated symbionts and reveal biosynthetic pathways.

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