Evaluation of Annona muricata Acetogenins as Potential Anti-SARS-CoV-2 Agents Through Computational Approaches

Annona muricata, a tropical plant which has been extensively used in ethnomedicine to treat a wide range of diseases, from malaria to cancer. Interestingly, this plant has been reported to demonstrate significant antiviral properties against the human immunodeficiency virus, herpes simplex virus, human papilloma virus, hepatitis C virus and dengue virus. Additionally, the bioactive compounds responsible for antiviral efficacy have also shown to be selectively cytotoxic while inhibiting tumorigenic cell growth without affecting the normal cell growth. Annonaceous Acetogenins are a class of bioactive compounds exclusive to the Annonaceae family at which the plant A. muricata belongs. In the current study, we have created a library of Acetogenins unique to the plant, comprising of Annomuricin A, Annomuricin B, Annomuricin C, Muricatocin C, Muricatacin, cis-Annonacin, Annonacin-10-one, cis-Goniothalamicin, Arianacin and Javoricin, for in silico and theoretical evaluations against the SARS-CoV-2 spike protein in an attempt toward promotion of plant based drug development for the current pandemic of coronavirus disease 2019 (COVID-19). We found that all the Acetogenins showing in silico spike protein significantly docking with good binding affinities. Moreover, we envision A. muricata Acetogenins can be further studied by in vitro and in vivo models to identify potential anti-SARS-CoV-2 agents.

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In Silico Assessment of ADME Properties: Advances in Caco-2 Cell Monolayer Permeability Modeling

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666181130140350 ◽

2019 ◽

Vol 18 (26) ◽

pp. 2209-2229 ◽

Cited By ~ 4

Author(s):

Hai Pham-The ◽

Miguel Á. Cabrera-Pérez ◽

Nguyen-Hai Nam ◽

Juan A. Castillo-Garit ◽

Bakhtiyor Rasulev ◽

...

Keyword(s):

Intestinal Absorption ◽

In Silico ◽

Review Paper ◽

Cell Monolayer ◽

Cell Permeability ◽

Drug Substances ◽

Wide Range ◽

Modeling Techniques

One of the main goals of in silico Caco-2 cell permeability models is to identify those drug substances with high intestinal absorption in human (HIA). For more than a decade, several in silico Caco-2 models have been made, applying a wide range of modeling techniques; nevertheless, their capacity for intestinal absorption extrapolation is still doubtful. There are three main problems related to the modest capacity of obtained models, including the existence of inter- and/or intra-laboratory variability of recollected data, the influence of the metabolism mechanism, and the inconsistent in vitro-in vivo correlation (IVIVC) of Caco-2 cell permeability. This review paper intends to sum up the recent advances and limitations of current modeling approaches, and revealed some possible solutions to improve the applicability of in silico Caco-2 permeability models for absorption property profiling, taking into account the above-mentioned issues.

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Andrographis paniculata (Burm. F.) Wall. Ex Nees, Andrographolide, and Andrographolide Analogues as SARS-CoV-2 Antivirals? A Rapid Review

Natural Product Communications ◽

10.1177/1934578x211016610 ◽

2021 ◽

Vol 16 (5) ◽

pp. 1934578X2110166

Author(s):

Xin Yi Lim ◽

Janice Sue Wen Chan ◽

Terence Yew Chin Tan ◽

Bee Ping Teh ◽

Mohd Ridzuan Mohd Abd Razak ◽

...

Keyword(s):

Inhibitory Activity ◽

In Silico ◽

Rna Binding ◽

Symptomatic Relief ◽

Andrographis Paniculata ◽

Spike Protein ◽

Rapid Review ◽

In Silico Studies

Drug repurposing is commonly employed in the search for potential therapeutic agents. Andrographis paniculata, a medicinal plant commonly used for symptomatic relief of the common cold, and its phytoconstituent andrographolide, have been repeatedly identified as potential antivirals against SARS-CoV-2. In light of new evidence emerging since the onset of the COVID-19 pandemic, this rapid review was conducted to identify and evaluate the current SARS-CoV-2 antiviral evidence for A. paniculata, andrographolide, and andrographolide analogs. A systematic search and screen strategy of electronic databases and gray literature was undertaken to identify relevant primary articles. One target-based in vitro study reported the 3CLpro inhibitory activity of andrographolide as being no better than disulfiram. Another Vero cell-based study reported potential SARS-CoV-2 inhibitory activity for both andrographolide and A. paniculata extract. Eleven in silico studies predicted the binding of andrographolide and its analogs to several key antiviral targets of SARS-CoV-2 including the spike protein-ACE-2 receptor complex, spike protein, ACE-2 receptor, RdRp, 3CLpro, PLpro, and N-protein RNA-binding domain. In conclusion, in silico and in vitro studies collectively suggest multi-pathway targeting SARS-CoV-2 antiviral properties of andrographolide and its analogs, but in vivo data are needed to support these predictions.

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Characterization of Andean Blueberry in Bioactive Compounds, Evaluation of Biological Properties and in vitro Bioaccessibility

10.20944/preprints202009.0055.v1 ◽

2020 ◽

Author(s):

Nieves Baenas ◽

Jenny Ruales ◽

Diego A. Moreno ◽

Daniel Alejandro Barrio ◽

Carla M. Stinco ◽

...

Keyword(s):

Antioxidant Capacity ◽

Bioactive Compounds ◽

Biological Activities ◽

In Vitro Digestion ◽

Biological Properties ◽

Wide Range ◽

Zebrafish Embryogenesis

Andean blueberries are wild berries grown and consumed in Ecuador which contain high values of bioactive compounds, mainly anthocyanins, with powerful antioxidant activity. The aim of this study was to evaluate the profile and contents of (poly)phenols and carotenoids in Andean blueberry by HPLC-DAD-MSn and determine a wide range of its biological activities. The antioxidant capacity of this fruit was evaluated in vitro by three different methods and in vivo using the zebrafish animal model, also the toxicity effect was determined by the zebrafish embryogenesis test. Besides, the antimicrobial activity and the capacity of Andean blueberry to produce hemagglutination in blood cells were evaluated. Finally, the bioaccessibility of (poly)phenols and related antioxidant capacity were determined in the different phases of an in vitro digestion. The global results indicated no toxicity of Andean blueberry, weakly bacteriostatic activity, and high contents of anthocyanins and antioxidant capacity, which were partially bioaccesible in vitro (~ 50 % at the final intestinal step), contributing to the knowledge of its health benefits for consumers and its potential use in the food and pharmaceutical industry as functional ingredient.

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Conformational Perturbation of SARS-CoV-2 Spike Protein Using N-Acetyl Cysteine, a Molecular Scissor: A Probable Strategy to Combat COVID-19

10.26434/chemrxiv.12687923.v1 ◽

2020 ◽

Author(s):

Utsab Debnath ◽

Varun Dewaker ◽

Yenamandra S. Prabhakar ◽

Parthasarathi Bhattacharyya ◽

Amit Mandal

Keyword(s):

Disulfide Bond ◽

In Silico ◽

Ex Vivo ◽

Virus Disease ◽

Spike Protein ◽

Early 21St Century ◽

Acetyl Cysteine ◽

Structural Architecture

The infection caused by Severe Acute Respiratory Syndrome–CoronaVirus-2 (SARS-CoV-2) resulted in a pandemic across the globe with a huge death toll. The symptoms from SARS-CoV2 appear somewhat similar to the SARS-CoV-1 infection that appeared in early 21st century but the infectivity is far higher for the SARS-CoV-2. The virus attaches itself to exposed human epithelial cells through the spike protein. Recently discovered crystal structure of the complex of spike protein of SARS-CoV-2 with human angiotensin-converting enzyme 2 (ACE2) receptor indicated that the virus binds with the host cell very strongly. We hypothesized that the perturbation of the functionally active conformation of spike protein through the reduction of a solvent accessible disulfide bond (Cys391-Cys525) that provides its structural architecture, may 2 be a feasible strategy to disintegrate the spike protein from ACE2 receptor and thereby prevent the infection. Using in silico platform we showed that N-acetyl cysteine (NAC), a drug used as antioxidant and mucolytic agent, binds in the close proximity of above disulfide bond. The reduction of the disulfide bond via thiol/disulfide exchange, followed by covalent conjugation of NAC perturbed the stereo specific orientations of interacting key residues of spike protein. This resulted in threefold weakening in the binding affinity of spike protein with ACE2 receptor. This opens avenues for exploring the effect of NAC in vitro, ex vivo and in vivo and on successful observation of the similar effect as in silico, the intervention of NAC may be translated in the pharmacoprevention and treatment of Corona virus disease 2019.

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Chloroform Fraction of Methanolic Extract of Seeds of Annona muricata Induce S Phase Arrest and ROS Dependent Caspase Activated Mitochondria Mediated Apoptosis in Triple Negative Breast Cancer

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200918101448 ◽

2020 ◽

Vol 20 ◽

Author(s):

Ajith J. George ◽

Bibu J. Kariyil ◽

Usha P.T. Ayyappan ◽

Anu Gopalakrishnan

Keyword(s):

Cell Cycle ◽

Cell Lines ◽

Triple Negative ◽

S Phase ◽

Chloroform Fraction ◽

Annona Muricata ◽

In Vivo Evaluation ◽

Annonaceous Acetogenins

Background: Triple negative breast cancers (TNBCs) are having high morbidity and shorter survival rate in the population. These types of cancers are having high aggressiveness, lymphatic invasion and absence of receptors. The treatment options for these types of cancers are also scarce. Several studies have been conducted to investigate the effectiveness of seeds of Annona muricata for its anti cancer activities in various cancer cell lines such as lung A549, breast MCF7, colon HT-29, oral KB and human hepatoma cell lines. But works related to its anticancer effect and mechanism of action in TNBCs has not been elucidated. Objective: The present study was undertaken to evaluate the in vitro, in vivo and in silico anticancer potential of chloroform fraction of methanolic extract of seeds of Annona muricata (CMAM) against TNBC along with elucidation of its mechanistic pathway. Methods: In vitro cytotoxicity- and antiproliferative- studies in three triple negative breast cancer cell lines were conducted using MTT and SRB assays respectively. The mechanism through which CMAM exerts its pharmacological effect was elucidated in vitro employing cell morphological assessment studies using acridine orange/ ethidium bromide (AO/EB), intra cellular reactive oxygen species assay, DNA fragmentation assay, agarose gel electrophoresis, terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay, cell cycle analysis, annexin binding assay and caspase activated mitochondria mediated apoptotic assays using western blot. In vivo evaluation in 4T1 induced murine mammary tumour model was also conducted. Phytoconstituents in CMAM was analysed using liquid chromatography mass spectroscopy. In silico binding studies with various annonaceous acetogenins against BCL-2 and cyclin E were performed. Results: Cytotoxicity studies in MDA-MD-231, 4TI and BT-549 revealed the IC50 value of CMAM to be 2.5±0.14, 4.8±0.3 and 4.5±0.16 µg/mL respectively. Anti proliferative studies in 4T1, MDA-MB-231 and BT-549 revealed the GI50 values to be 0.128+0.03, 18.03+0.20, 0.95+0.04 µg/mL respectively. CMAM exhibited its cytotoxicity through the lysis of cell membrane, ROS dependent caspase activated mitochondria mediated apoptosis, and arresting the S phase of the cell cycle. In vivo evaluation also supported the tumoricidal property of CMAM as evidenced by reduction in tumour volume and serum biomarkers. Histopathologically there was a marked reduction in cellularity, nuclear chromatin condensation and a few normal cells in group treated with CMAM at a dose of 31mg/Kg. Phytoconstituent evaluation has revealed the presence of annonaceous acetogenins in CMAM. Among the various annonaceous acetogenins, muricatacin alone showed lipophilicity and binding affinity towards BCL-2 and cyclin E1. Conclusion: The current study shows the effectiveness of CMAM against TNBC both in vitro and in vivo. This anticancerous effect of CMAM could be by virtue of its ROS dependent caspase activated mitochondria mediated apoptosis and the S-phase arrest of the cell cycle in the TNBCs. Our results indicate that the presence of annonaceous acetogenins, especially muricatacin, could be contributing to this anticanceros effect of CMAM. Thus muricatacin could be a potential candidate for the targeted therapy of TNBCs.

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Evaluation of antitumor and anti-angiogenic activity of bioactive compounds from Cinnamomum tamala : In vitro , in vivo and in silico approach

South African Journal of Botany ◽

10.1016/j.sajb.2015.09.014 ◽

2016 ◽

Vol 104 ◽

pp. 6-14 ◽

Cited By ~ 9

Author(s):

Deepavali Thanekar ◽

Jayesh Dhodi ◽

Nitin Gawali ◽

Archana Raju ◽

Padmini Deshpande ◽

...

Keyword(s):

Bioactive Compounds ◽

In Silico ◽

Angiogenic Activity ◽

Cinnamomum Tamala

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Current model systems for the study of preeclampsia

Experimental Biology and Medicine ◽

10.1177/1535370218755690 ◽

2018 ◽

Vol 243 (6) ◽

pp. 576-585 ◽

Cited By ~ 7

Author(s):

ML Martinez-Fierro ◽

GP Hernández-Delgadillo ◽

V Flores-Morales ◽

E Cardenas-Vargas ◽

M Mercado-Reyes ◽

...

Keyword(s):

Blood Pressure ◽

Endothelial Dysfunction ◽

In Silico ◽

Complex Disease ◽

Model Systems ◽

Trophoblast Invasion ◽

Wide Range ◽

In Silico Models

Preeclampsia (PE) is a pregnancy complex disease, distinguished by high blood pressure and proteinuria, diagnosed after the 20th gestation week. Depending on the values of blood pressure, urine protein concentrations, symptomatology, and onset of disease there is a wide range of phenotypes, from mild forms developing predominantly at the end of pregnancy to severe forms developing in the early stage of pregnancy. In the worst cases severe forms of PE could lead to systemic endothelial dysfunction, eclampsia, and maternal and/or fetal death. Worldwide the fetal morbidity and mortality related to PE is calculated to be around 8% of the total pregnancies. PE still being an enigma regarding its etiology and pathophysiology, in general a deficient trophoblast invasion during placentation at first stage of pregnancy, in combination with maternal conditions are accepted as a cause of endothelial dysfunction, inflammatory alterations and appearance of symptoms. Depending on the PE multifactorial origin, several in vitro, in vivo, and in silico models have been used to evaluate the PE pathophysiology as well as to identify or test biomarkers predicting, diagnosing or prognosing the syndrome. This review focuses on the most common models used for the study of PE, including those related to placental development, abnormal trophoblast invasion, uteroplacental ischemia, angiogenesis, oxygen deregulation, and immune response to maternal–fetal interactions. The advances in mathematical and computational modeling of metabolic network behavior, gene prioritization, the protein–protein interaction network, the genetics of PE, and the PE prediction/classification are discussed. Finally, the potential of these models to enable understanding of PE pathogenesis and to evaluate new preventative and therapeutic approaches in the management of PE are also highlighted. Impact statement This review is important to the field of preeclampsia (PE), because it provides a description of the principal in vitro, in vivo, and in silico models developed for the study of its principal aspects, and to test emerging therapies or biomarkers predicting the syndrome before their evaluation in clinical trials. Despite the current advance, the field still lacking of new methods and original modeling approaches that leads to new knowledge about pathophysiology. The part of in silico models described in this review has not been considered in the previous reports.

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In silico Screening of Food Bioactive Compounds to Predict Potential Inhibitors of COVID-19 Main protease (Mpro) and RNA-dependent RNA polymerase (RdRp)

10.26434/chemrxiv.12051927.v2 ◽

2020 ◽

Cited By ~ 4

Author(s):

Brahmaiah Pendyala ◽

Ankit Patras

Keyword(s):

Rna Polymerase ◽

Bioactive Compounds ◽

In Silico ◽

World Health ◽

Rna Dependent Rna Polymerase ◽

In Silico Screening ◽

Main Protease ◽

Health Organization

As novel corona virus (COVID-19) infections has spread throughout the world, world health organization (WHO) has announced COVID-19 as a pandemic infection. Henceforth investigators are conducting extensive research to find possible therapeutic agents against COVID-19. Main protease (Mpro) that plays an essential role in processing the polyproteins that are translated from the 2019-nCOV RNA and RNA-dependent RNA polymerase (RdRp) that catalyzes the replication of RNA from RNA template becomes as a potential targets for in silico screening of effective therapeutic compounds to COVID-19. In this study we used COVID-19 Docking Server to predict potential food bioactive compounds to inhibit Mpro and RdRp. The results showed that Phycocyanobilin, Riboflavin, Cyanidin, Daidzein, Genistein are potent inhibitor bioactive compounds to Mpro and RdRp in comparison to antiviral drugs. Though, further in vitro and/or in vivo research is required to validate the docking results.

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In silico Screening of Food Bioactive Compounds to Predict Potential Inhibitors of COVID-19 Main protease (Mpro) and RNA-dependent RNA polymerase (RdRp)

10.26434/chemrxiv.12051927 ◽

2020 ◽

Cited By ~ 1

Author(s):

Brahmaiah Pendyala ◽

Ankit Patras

Keyword(s):

Rna Polymerase ◽

Bioactive Compounds ◽

In Silico ◽

World Health ◽

Rna Dependent Rna Polymerase ◽

In Silico Screening ◽

Main Protease ◽

Health Organization

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Targeting Virus-Host Interaction: An in Silico Approach to Develop Promising Inhibitors Against COVID-19

10.26434/chemrxiv.12198369 ◽

2020 ◽

Author(s):

Jitendra Subhash Rane ◽

Aroni Chatterjee ◽

Rajni Khan ◽

Abhijeet Kumar ◽

Shashikant Ray

Keyword(s):

Angiotensin Converting Enzyme ◽

In Silico ◽

Virus Disease ◽

Spike Protein ◽

Converting Enzyme ◽

Host Cell Membrane ◽

Angiotensin Converting Enzyme 2 ◽

Host Interaction

The entire human population all over the globe is currently facing appalling conditions due to the spread of infection from COVID-19 (corona virus disease-2019). In the last few months enormous amount of studies have been continuously trying to target several potential drug sites to identify a novel therapeutic target. Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is also being targeted by several scientific groups as a novel drug target. The spike glycoprotein protein is present on the surface of the virion and binds to the human angiotensin-converting enzyme-2 (hACE2) membrane receptor thereby promoting its fusion to the host cell membrane. The binding and internalization of the virus is a crucial step in the process of infection and hence any molecule that can inhibit this, certainly holds a significant therapeutic value. We have identified AP-NP (2-(2-amino-5-(naphthalen-2- yl)pyrimidin-4-yl)phenol) and AP-4-Me-Ph (2-(2-amino-5-(p-tolyl)pyrimidin-4-yl)phenol) from a group of diaryl pyrimidine derivatives which appear to bind at the interface of hACE2-SARS-CoV-2S complex (human angiotensin converting enzyme 2 and spike glycoprotein complex) with a low binding energy (<-8 Kcal/mol). In this in-silico study we also found that AP-NP interacts with S1 domain of C-terminal part of SARS-CoV-2S however AP-4-Me-Ph was found to interact with S2 domain of SARS-CoV-2S. The result suggested that AP-NP and AP-4-Me-Ph have potential to inhibit the interaction between spike protein and hACE2 receptor also AP-4-Me-Ph might be prevent internalization of the virion within the host. Further in vitro and in vivo study will strengthen these drug candidates against the COVID-19.

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