An in silico investigation to identify promising inhibitors for SARS-CoV-2 Mpro target.

BACKGROUND: A limited number of small molecules against SARS-CoV-2 has been discovered since the epidemic commenced in November 2019. The conventional medicinal chemistry approach demands more than a decade of the year of laborious research and development and a substantial financial commitment, which is not achievable in the face of the current epidemic. OBJECTIVE: This study aims to discover and recognize the most effective and promising small molecules by interacting SARS-CoV-2 Mpro target through computational screening of 39 phytochemicals from five different Ayurveda medicinal plants. METHODS: The phytochemicals were downloaded from PubChem, and the SARS-CoV-2 protein (PDB ID: 6LU7; Mpro) was taken from the PDB. The molecular interactions, binding energy, and ADMET properties were analyzed. RESULTS: The binding affinities were studied using a structure-based drug design of molecular docking, divulging 21 molecules possessing greater to equal affinity towards the target than the reference standard. Molecular docking analysis identified 13 phytochemicals, sennoside-B (-9.5 kcal/mol), isotrilobine (-9.4 kcal/mol), trilobine (-9.0 kcal/mol), serratagenic acid (-8.1 kcal/mol), fistulin (-8.0 kcal/mol), friedelin (-7.9 kcal/mol), oleanolic acid (-7.9 kcal/mol), uncinatone (-7.8 kcal/mol), 3,4-di-O-caffeoylquinic acid (-7.4 kcal/mol), clemaphenol A (-7.3 kcal/mol), pectolinarigenin (-7.2 kcal/mol), leucocyanidin (-7.2 kcal/mol), and 28-acetyl botulin (-7.2 kcal/mol) from Ayurvedic medicinal plants phytochemicals possess greater affinity than (-7.0 kcal/mol) against SARS-CoV-2-Mpro. CONCLUSION: Two molecules, namely sennoside-B, and isotrilobine with low binding energies, were the most promising. Furthermore, we carried out molecular dynamics simulations for the sennoside-B protein complexes based on the docking score. ADMET properties prediction confirmed that the selected docked phytochemicals were optimal. These compounds can be investigated further and utilized as a parent core molecule to create novel lead molecules for preventing COVID-19.

Dual Modulators of Selected Plant Secondary Metabolites Targeting COVID-19 Main Protease and Interleukin-2: An In-Silico Approach based Novel Hypothesis

Background: Owing to the recent scenario on this ongoing Coronavirus pandemic outbreak around the world, the present study has been undertaken. Aim(s): In this study, we adopted two strategies, i.e., via computational method, a search for the novel plant secondary metabolites from the Indian Traditional Medicine to target and combat the enduring novel 2019 CoVs main protease that causes pneumonia, followed by the effect of these selected secondary metabolites on the host's immune system for their immunomodulatory potential on Interleukin-2. Method(s): A detailed literature review has been done to identify the assorted plant secondary metabolites from the natural sources, which have been extensively used traditionally for their immunomodulatory potential. Next, the resulting compounds have processed for the molecular docking study to predict whether the compounds have the potency to fight against 2019-CoVs protein or it could have the ten-dency to battle the cytokines, which are responsible for the immune response of the host, thereby pre-venting the CoVs caused infection in humans. Furthermore, to explore molecular mechanics, the in-silico docking study with COVID-19 Mpro and Interleukin-2 has been performed. Results & Discussion: Among the six secondary metabolites selected, five compounds showed its possible promising potency with COVID-19 and IL-2 proteins, which are compared with the standard drug Remdesivir, one of the anti-viral drugs for treating and managing the present coronavirus condition and an IL-2 inhibitor, which is the native IL-2 ligand protein (i.e., from PDB Id-1PW6) itself. Besides, based on the docking scores, the Curcumin (from Curcuma longa) showed the highest score towards these two targets taken for this study. The identified compounds have a promising binding affinity with the Mpro receptors, in the narrow range of binding energy for the protein PDB Id: 6LU7 and the score range between-10.9102 to-19.8790 kcal/mol: when compared to the standard-21.8600 kcal/mol. Whereas, the binding affinity with the Interleukin-2 receptor, for the protein PDB Id: 1PW6 the range between-11.3899 to-17.1366 kcal/mol: when compared to that of standard-16.9554 kcal/mol. Conclusion(s): Our result findings demonstrate that the integrated Indian traditional herbal treatment might be hopefully used for the viral respiratory infection due to either it may have acted directly on the viral protein or through regulating the immune response, which could lead to the rapid drug discovery of the drug leads with clinical potency towards the novel infectious disease, where there is no drug or vaccines are available.Copyright © 2021 Bentham Science Publishers.

Design and synthesis of novel quercetin metal complexes as IL-6 inhibitors for anti-inflammatory effect in SARS-CoV-2

One of the most common causes of mortality in COVID-19 patients is cytokine release syndrome (CRS). Though several cytokines are involved in CRS, the role of Interleukin 6 is significant. Considering the importance of IL-6 inhibition and the drawbacks of the existing monoclonal antibodies, the present study develops new flavonoid metal complexes as immune boosters targeting IL-6 for SARS-CoV-2 treatment. To identify the potential flavonoids from 152 secondary plant metabolites, PyRx 0.9 tool has been used. The top scorer quercetin was converted into quercetin-oxime. Seven metal complexes (QM-1 to QM-7) were made from quercetin-oxime by utilizing divalent metals such as zinc, copper, magnesium, cobalt, barium, and cadmium. It was assumed that all compounds were moderately soluble and would not penetrate the BBB through in silico ADME studies. However, the in vitro heamolytic research revealed a modest heamolytic effect in all seven complexes. To know the IL-6 inhibitory potential preliminary level, the complexes were screened for cytotoxicity in cell lines MCF-7 which predominantly expresses the IL-6 level. The cytotoxic effects of all complexes were considerable relative to the marketable Nutridac formulation. The complexes quercetin-Zinc (QM1) and quercetin-Zinc-Ascorbic acid (QM7) showed significant cytotoxicity on MCF-7 compared to Nutridac and no cytotoxic toward the normal cell lines. © 2022, National Institute of Science Communication and Policy Research. All rights reserved.

Dual Modulation of IL-6 Pathway by Flavonoid Metal Complex as Immune Boosters for SARS-CoV-2 Therapy

It is observed that cytokine release syndrome (CRS) is one of the major causes of the death of several COVID-19 patients. Though several cytokines are involved in CRS, IL-6 modulation plays a major role. We aim to develop new flavonoid metal complexes as immune boosters targeting IL-6 for SARS-CoV-2 treatment. To find potential flavonoids, PyRx 0.9 tool has been used to dock 152 secondary plant metabolites against IL-6 (PDB ID: 1ALU). The top scorer flavonoid (quercetin) was made into quercetin zinc ascorbic acid metal complex (QM-1). The in-vitro hemolytic research revealed a modest hemolytic effect in the QM1 metal complex. To control the IL-6 inhibitory potential, the QM1 complex was screened for cytotoxicity in cell lines MCF-7 which predominantly expresses the IL-6 level. The cytotoxic effects of the QM1 complex were considered relative to the marketable Nutridac formulation. The complex quercetin-Zinc-Ascorbic acid (QM1) significantly affected MCF-7 cells in concentrations 48.54 μg/mL, respectively. © The Electrochemical Society

Discovery of Immunomodulators from Plant Kingdom Targeting IL-6 for the Effective Management Therapy of SARS-CoV-2

The present study was conducted because of the recent scenario of this pandemic coronavirus outbreak worldwide. Currently, this disease cannot be treated through specific vaccines and therapeutic medicines. While many vaccines are being investigated, it would take some time for these to be accessible to the masses. Eventual evidence indicates that many COVID-19 patients may die from an irregular release of cytokines called as Cytokine Release Syndrome (CRS) due to the excessive reaction of their immune systems. In worsening patients with COVID-19, CRS played a significant role, from pneumonia via ARDS to cumulative systemic inflammation and eventually to a failing of the multi-system organ. In COVID-19 individuals, a large number of cytokines, including IL-6, IL-1, IL-2, IL-10, TNF-α, and IFN-α, participate in the ‘cytokine storm,’ but IL-6, whose higher serum levels are associated with respiratory failure, ARDS, and adverse clinical outcomes, tends to be a critical factor. In China, the COVID-19 mortality indicator has been tested by a multi-centre retrospective analysis in 150 COVID-19 patients. The study analysed that 82 cases are resolved from COVID-19 and 68 cases are dead due to enhancement of IL-6 levels in the serum. In this research, the secondary plant metabolites from Indian traditional medicine are identified through a computational technique and the selected seedling metabolite is sealed to block the IL-6 receptor. © 2022, Informatics Publishing Limited. All rights reserved.

Hydroxychloroquine and curcumin conjugates as multifunctional co drugs for the potential treatment of COVID-19: An in-silico based study

The present study has been undertaken to search the novel co drugs for fight-ing against the COVID-19 disease through an in-silico approach. We have designed eight co drugs by merging two drugs namely hydroxychloroquine, used in the treatment of COVID-19 and curcumin an immuno modulator. The two drugs were linked through a bio-cleavable hydrolyzable linker by three-step process. The designed co drugs were subjected for molecular docking studies to know their therapeutic efficacy against the COVID-19 main protease (Mpro) and Interleukin-1β. The designed co drugs have a promising binding affinity towards Mpro in the narrow range of binding energies between-28.2498 to-35.8648 kcal/mol when compared to the standard Remdesivir which has-21.8600 kcal/mol. Similarly the binding energies of designed co drugs against Interleukin-1β range between-25.8032 to-34.6973 kcal/mol when compared to the standard curcumin which has-17.3274 kcal/mol. Our findings demonstrated that the designed co drugs may be useful for the treatment of viral respiratory infection due to their additive therapeutic actions on the viral protein and modulating the immune response synergistically.