scholarly journals ACTIVITY SCREENING AND STRUCTURE MODIFICATION OF ARTOCARPIN AGAINST ACE2 AND MAIN PROTEASE THROUGH IN SILICO METHOD

2021 ◽  
pp. 192-198
Author(s):  
MUHAMMAD FAUZI ◽  
ARIS FADILLAH ◽  
FAUZI RAHMAN ◽  
JUWITA RAMADHANI ◽  
KARINA ERLIANTI ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
In Silico ◽  
Docking Simulation ◽  
Positive Control ◽  
Hydroxyl Group ◽  
Artocarpus Altilis ◽  
Main Protease ◽  
Activity Screening ◽  
The Stability ◽  
The Right

Objective: SARS-CoV-2 is a type of coronavirus that causes COVID-19 disease. Currently, the right and effective drug for the treatment of COVID-19 has not been found. Artocarpin in the breadfruit plant (Artocarpus altilis), which was tested, has been shown to have antiviral activity. However, artocarpin has a hydroxyl group that can undergo oxidation within a certain time, thereby reducing the stability of the compound and non-specific antiviral activity. Methods: In this study, the structural modification of artocarpin was carried out to obtain compounds with anticoronavirus activity with good physicochemical properties. This research was conducted in silico, including molecular docking simulation, bioavailability prediction, and preADMET. Results: The top 20 modified compounds were selected from each target's top 3 compounds, which had better bond energies compared to the positive control. These 3 compounds have the potential to inhibit ACE2 and Mpro receptors and 1 compound are better at inhibiting both. Conclusion: From the results of the research conducted, we conclude that the 3 best compounds can be potential candidates that can be developed as COVID-19 therapy.

In silico screening of phytoconstituents with antiviral activities against SARS-COV-2 main protease, Nsp12 polymerase and Nsp13 helicase proteins

2021 ◽  
Vol 18 ◽  
Author(s):  
Jainey James ◽  
Divya Jyothi ◽  
Sneh Priya
Keyword(s):  
Antiviral Activity ◽  
Molecular Interactions ◽  
In Silico ◽  
Antiviral Treatment ◽  
In Vivo Studies ◽  
Main Protease ◽  
Hypothesis Model ◽  
Antiviral Activities ◽  
Pharmacophore Hypothesis

Aims: The present study aim was to analyse the molecular interactions of the phytoconstituents known for their antiviral activity with the SARS-CoV-2 nonstructural proteins such as main protease (6LU7), Nsp12 polymerase (6M71), and Nsp13 helicase (6JYT). The applied in silico methodologies was molecular docking and pharmacophore modeling using Schrodinger software. Methods: The phytoconstituents were taken from PubChem, and SARS-CoV-2 proteins were downloaded from the protein data bank. The molecular interactions, binding energy, ADMET properties and pharmacophoric features were analysed by glide XP, prime MM-GBSA, qikprop and phase application of Schrodinger respectively. The antiviral activity of the selected phytoconstituents was carried out by PASS predictor, online tools. Results: The docking score analysis showed that quercetin 3-rhamnoside (-8.77 kcal/mol) and quercetin 3-rhamnoside (-7.89 kcal/mol) as excellent products to bind with their respective targets such as 6LU7, 6M71 and 6JYT. The generated pharmacophore hypothesis model validated the docking results, confirming the hydrogen bonding interactions of the amino acids. The PASS online tool predicted constituent's antiviral potentials. Conclusion: The docked phytoconstituents showed excellent interactions with the SARS-CoV-2 proteins, and on the outset, quercetin 3-rhamnoside and quercetin 7-rhamnoside have well-interacted with all the three proteins, and these belong to the plant Houttuynia cordata. The pharmacophore hypothesis has revealed the characteristic features responsible for their interactions, and PASS prediction data has supported their antiviral activities. Thus, these natural compounds could be developed as lead molecules for antiviral treatment against SARS-CoV-2. Further in-vitro and in-vivo studies could be carried out to provide better drug therapy.

scholarly journals Potential Smoothened Inhibitor from Traditional Chinese Medicine against the Disease of Diabetes, Obesity, and Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Mao-Feng Sun ◽  
Hsin-Yi Chen ◽  
Cheng-Chun Lee ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Drug Development ◽  
Hedgehog Signaling ◽  
Docking Simulation ◽  
Md Simulations ◽  
Positive Control ◽  
Lead Compounds ◽  
Oncology Clinical Trials ◽  
Body Patterning ◽  
The Stability ◽  
Smo Inhibitor

Nowadays, obesity becomes a serious global problem, which can induce a series of diseases such as type 2 diabetes mellitus, cancer, cardiovascular disease, metabolic syndrome, and stoke. For the mechanisms of diseases, the hedgehog signaling pathway plays an important role in body patterning during embryogenesis. For this reason, smoothened homologue (Smo) protein had been indicated as the drug target. In addition, the small-molecule Smo inhibitor had also been used in oncology clinical trials. To improve drug development of TCM compounds, we aim to investigate the potent lead compounds as Smo inhibitor from the TCM compounds in TCM Database@Taiwan. The top three TCM compounds, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid), have displayed higher potent binding affinities than the positive control, LY2940680, in the docking simulation. After MD simulations, which can optimize the result of docking simulation and validate the stability of H-bonds between each ligand and Smo protein under dynamic conditions, top three TCM compounds maintain most of interactions with Smo protein, which keep the ligand binding stable in the binding domain. Hence, we propose precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid) as potential lead compounds for further study in drug development process with the Smo protein.

scholarly journals Repurposing of Anthelmintic Drugs against SARS-CoV-2 (Mpro and RdRp): Novel Disease, Older Therapeutics

2020 ◽  
Vol 10 (2) ◽  
pp. 2331-2338
Keyword(s):  
Antiviral Activity ◽  
Protease Inhibitor ◽  
In Silico ◽  
Rna Polymerases ◽  
The Novel ◽  
Inhibitor Activity ◽  
Main Protease ◽  
Promising Target ◽  
Potential Inhibitors ◽  
Anthelmintic Drugs

Since late December 2019, the entire nations are facing the novel enemy of COVID-19, which has imposed a tremendous burden on the researchers across the globe to develop a treatment for it. Recognition of main protease and RNA dependent RNA polymerases as a promising target of SARS-CoV-2 encouraged us to repurpose some older antihelmintic drugs against COVID-19. In this constructive research, we have investigated anthelmintic drugs' antiviral activity, including ivermectin, doramectin, and selamectin, for their antiviral potential against SARS-CoV-2 by employing in silico tools. The selected drugs, including ivermectin, doramectin, and selamectin, were encountered as potential inhibitors of SARS-CoV-2 RNA-dependent RNA polymerases with an affinity of -9.2, -10.0, and -10.2 kcal/mol. They were found to exhibit main protease inhibitor activity with an affinity of -8.3, -8.7, and -9.0, respectively. Thus, using the repurposing approach in conjugation within silico tools, we have proposed ivermectin, doramectin, and selamectin as potential antivirals against SARS-CoV-2.

scholarly journals Drug design: 4-thiazolidinones applications. Part 2. Pharmacological profiles

2020 ◽  
Vol 89 (2) ◽  
pp. e407 ◽  
Author(s):  
Roman Lesyk
Keyword(s):  
Antiviral Activity ◽  
In Silico ◽  
Structure Optimization ◽  
Chemical Diversity ◽  
Anticancer Effect ◽  
Lead Compounds ◽  
Fused Heterocycles ◽  
Hybrid Molecules ◽  
Pharmacological Data ◽  
Activity Screening

Following of the chemical diversity of 4-thiazolidinones the in-house library of new heterocycles have been designed and synthesized (more 7000 compounds). Anticancer, antitrypanosomal, antituberculosis and antiviral activity screening led to SAR database formation; lead-compounds identification; design of focused sub-libraries; formation and validation of hypotheses for structure optimization: i) complications of C5 fragment and/or functionalization of N3 position; ii) creation of the hybrid molecules; iii) fixation of 5-ene-4-thiazolidinones in fused heterocycles via annulation (thiopyrano[2,3-d]thiazoles were found as a cyclic isosteric mimetics of 5-ene-4-thiazolidinones); iv) the leukemia panel was detected to be the most sensitive among all cancer cell lines. Following the in silico and pharmacological data for the investigation of molecular mechanism of anticancer effect the argument in favor of the apoptotic related and mild prooxidant actions for active compounds have been found.

scholarly journals Molecular Docking Terhadap Senyawa Kurkumin dan Arturmeron pada Tumbuhan Kunyit (Curcuma Longa Linn.) yang Berpotensi Menghambat Virus Corona

2021 ◽  
Vol 9 (2) ◽  
Author(s):  
Tiara C. Pradani ◽  
. Fatimawali ◽  
Aaltje E. Manampiring ◽  
Billy J. Kepel ◽  
Fona D. Budiarso ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
In Silico ◽  
Virus Disease ◽  
Curcuma Longa ◽  
Positive Control ◽  
Tropical Plant ◽  
Corona Virus ◽  
Main Protease ◽  
Close Relationship

Abstract: At the end of 2019 the world was shocked by the emergence of a new virus, namely the corona virus (SARS-CoV 2) which is called Corona Virus Disease 2019 or COVID-19. The origin of the emergence of this virus is known to have originated in the city of Wuhan, Hubei Province, China in December 2019.1 Research shows a close relationship with the corona virus that causes Severe Acute Respitatory Syndrome (SARS) which broke out in Hong Kong in 2003, until WHO named it the novel corona virus ( nCoV19). Turmeric (Curcuma longa L.) is a tropical plant that has many benefits and is found in many parts of Indonesia. Turmeric is widely used by the community as a traditional medicine to treat several diseases, such as: anti-inflammatory, antioxidant, hepatoprotective, and others. This study aims to determine the content in several compounds in the turmeric plant that have the potential to inhibit COVID-19 by using the molecular docking method. Using the In Silico method, namely molecular docking with the compounds taken were curcumin and ar-turmerone and the main protease COVID-19 (6LU7). This study obtained the binding affinity of curcumin compounds, namely -7.2 and Ar-turmerone -5.8 compounds against Mpro COVID-19. Remdesivir, which was used as a positive control, had a binding affinity of -7.7. In conclusion, remdesivir got better results compared to curcumin and Ar-turmerone compounds.Keywords: Molecular Docking, Turmeric, COVID-19.  Abstrak: Pada akhir tahun 2019 dunia digemparkan dengan munculnya virus baru yaitu corona virus (SARS-CoV 2) yang disebut dengan Corona Virus Disease 2019 atau COVID-19. Awal mula munculnya virus ini diketahui berasal dari Kota Wuhan, Provinsi Hubei, China pada Desember 2019.1  Penelitian menunjukkan hubungan yang dekat dengan virus corona penyebab Severe Acute Respitatory Syndrome (SARS) yang mewabah di Hongkong pada tahun 2003, hingga WHO menamakannya sebagai novel corona virus (nCoV19). Kunyit (Curcuma longa L.) merupakan salah satu jenis tanaman tropis yang banyak memiliki manfaat dan banyak ditemukan di wilayah Indonesia. Kunyit banyak dimanfaatkan masyarakat sebagai obat tradisional untuk mengobati beberapa penyakit seperti: antiinflamasi, antioksidan, hepatoprotektor, dan lain-lain. Penelitian ini bertujuan untuk mengetahui kandungan dalam beberapa senyawa pada tumbuhan kunyit yang berpotensi menghambat COVID-19 dengan metode molecular docking. Menggunakan metode In Silico yaitu molecular docking dengan senyawa yang diambil adalah kurkumin dan ar-Turmerone dan main protease COVID-19 (6LU7). Penelitian ini didapatkan hasil binding affinity senyawa kurkumin yaitu -7.2 dan senyawa ar-turmeron -5.8 terhadap Mpro COVID-19. Remdesivir yang digunakan sebagai control positif mendapatkan hasil binding affinity yaitu -7.7. Sebagai simpulan, remdesivir mendapat hasil yang lebih baik dibandingkan dengan senyawa kurkumin dan ar-turmeron.Kata Kunci: Molecular Docking, Kunyit, COVID-19.

scholarly journals In-Silico Evaluation of Tiryaq-E-Wabai, an Unani Formulation for its Potency against SARS-CoV-2 Spike Glycoprotein and Main Protease

2021 ◽  
Vol 11 (4-S) ◽  
pp. 86-100
Author(s):  
N ZAHEER AHMED ◽  
DICKY JOHN DAVIS ◽  
NOMAN ANWAR ◽  
ASIM ALI KHAN ◽  
RAM PRATAP MEENA ◽  
...  
Keyword(s):  
In Silico ◽  
Dynamics Simulation ◽  
In Vivo Studies ◽  
Spike Glycoprotein ◽  
Unani Medicine ◽  
Main Protease ◽  
Pubchem Database ◽  
The Stability

COVID-19 was originated in Wuhan, China, in December 2019 and has been declared a pandemic disease by WHO. The number of infected cases continues unabated and so far, no specific drug approved for targeted therapy. Hence, there is a need for drug discovery from traditional medicine. Tiryaq-e-Wabai is a well-documented formulation in Unani medicine for its wide use as prophylaxis during epidemics of cholera, plague and other earlier epidemic diseases. The objective of the current study is to generate in-silico evidence and evaluate the potency of Tiryaq-e-Wabai against SARS-CoV-2 spike (S) glycoprotein and main protease (3CLpro). The structures of all phytocompounds used in this study were retrieved from PubChem database and some were built using Marvin Sketch. The protein structure of the SARS-CoV-2 S glycoprotein and 3CLpro was retrieved from the PDB ID: 6LZG and 7BQY respectively. AutoDock Vina was used to predict top ranking poses with best scores. The results of the molecular docking showed that phytocompounds of Tiryaq-e-Wabai exhibited good docking power with spike glycoprotein and 3CLpro. Among tested compounds Crocin from Zafran and Aloin A from Sibr showed strong binding to spike glycoprotein and 3CLpro respectively. Molecular dynamics simulation confirmed the stability of the S glycoprotein-Crocin and 3CLpro-Aloin A complexes. The Unani formulation Tiryaq-e-Wabai has great potential to inhibit the SARS-CoV-2, which have to be substantiated with further in-vitro and in-vivo studies. Keywords: In-silico study, SARS-CoV-2, Tiryaq-e-Wabai, Unani formulation, Crocin, Aloin A

scholarly journals Evaluation of the Novel Synthetic Tyrosinase Inhibitor (Z)-3-(3-bromo-4-hydroxybenzylidene)thiochroman-4-one (MHY1498) In Vitro and In Silico

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3307 ◽  
Author(s):  
EunJin Bang ◽  
Sang-Gyun Noh ◽  
Sugyeong Ha ◽  
Hee Jung ◽  
Dae Kim ◽  
...  
Keyword(s):  
In Silico ◽  
Docking Simulation ◽  
Positive Control ◽  
Tyrosinase Activity ◽  
Inhibition Mechanism ◽  
The Novel ◽  
Melanin Synthesis ◽  
Chemical Structures ◽  
Tyrosinase Inhibitors

Tyrosinase is a key enzyme in melanin synthesis, catalyzing the initial rate-limiting steps of melanin synthesis. Abnormal and excessive melanin synthesis is the primary cause of serious skin disorders including melasma, senile lentigo, freckles, and age spots. In attempts to find potent and safe tyrosinase inhibitors, we designed and synthesized a novel compound, (Z)-3-(3-bromo-4-hydroxybenzylidene)thiochroman-4-one (MHY1498), and evaluated its tyrosinase inhibitory activity in vitro and in silico. The chemical structures of (Z)-3-benzylidenethiochroman-4-one analogues, including the novel compound MHY1498, were rationally designed and synthesized as hybrid structures of reported potent tyrosinase inhibitors, which were confirmed both in vitro and in vivo: (Z)-5-(substituted benzylidene)thiazolidine-2,4-diones (Compound A) and 2-(substituted phenyl)benzo[d]thiazoles (Compound B). During screening, MHY1498 showed a strong dose-dependent inhibitory effect on mushroom tyrosinase. The IC50 value of MHY1498 (4.1 ± 0.6 μM) was significantly lower than that of the positive control, kojic acid (22.0 ± 4.7 μM). In silico molecular multi-docking simulation and inhibition mechanism studies indicated that MHY1498 interacts competitively with the tyrosinase enzyme, with greater affinity for the active site of tyrosinase than the positive control. Furthermore, in B16F10 melanoma cells treated with α-melanocyte-stimulating hormone, MHY1498 suppressed both melanin production and tyrosinase activity. In conclusion, our data demonstrate that MHY1498, a synthesized novel compound, effectively inhibits tyrosinase activity and has potential for treating hyperpigmentation and related disorders.

scholarly journals In Silico Activity Identification of Cyclo Peptide Alkaloids from Zizyphus Spina-Christi Species Against Sars-Cov-2 Main Protease

2021 ◽  
Vol 6 (1) ◽  
pp. 71-81
Author(s):  
Taufik Muhammad Fakih ◽  
Dwi Syah Fitra Ramadhan ◽  
Fitrianti Darusman
Keyword(s):  
In Silico ◽  
Density Functional ◽  
Docking Simulation ◽  
Functional Theory ◽  
Main Protease ◽  
Docking Method ◽  
Promising Target ◽  
Cyclopeptide Alkaloids ◽  
Prediction Server ◽  
Native Ligand

The COVID-19 has spread worldwide and become an international pandemic. The promising target for drug discovery of COVID-19 was SARS-CoV-2 Main Protease (Mpro), that has been successfully crystallized along with its inhibitor. The discovery of peptide-based inhibitors may present better options than small molecules for inhibitor SARS-CoV-2 Mpro. Natural compounds have such a wide potential and still few explored, Zizyphus spina-christi is one of the medicinal plants that have many pharmacological activities and contains a peptide compound from alkaloids class, i.e. cyclopeptide alkaloids, that is interesting to explore as SARS-CoV-2 Mpro inhibitor. The compound structure was drawn and optimized using density functional theory 3-21G method. The protein chosen was the high resolution of SARS-CoV-2 MPro receptor (1.45 Å) with PDB ID: 6WNP, in complex with boceprevir. Molecular docking simulation was performed using Autodock4 with 100 numbers of GA run, the validation methods assessed by RMSD calculation. Furthermore, the prediction of pharmacological activity spectra was carried out using the PASS Prediction server. The results showed RMSD value was 1.98 Å, this docking method was valid. The binding energy of all compounds showed better results than the native ligand (Boceprevir). The in silico PASS prediction results indicated that all compounds showed antiviral activity. Some compounds showed protease inhibitory activity, i.e Ambiphibine-H, Franganine, and Mauritine-A, and the highest Pa (Predicted activity) value showed by Mauritine-A compounds. It can be concluded that the cyclopeptide compounds of Zizyphus spina-christi were indicated to have a potential as COVID-19 therapy targeting SARS-CoV-2 Mpro.

scholarly journals Potential Drugs Against COVID-19 Revealed by Gene Expression Profile, Molecular Docking and Molecular Dynamic Simulation

2020 ◽  
Author(s):  
Claudia Cava ◽  
Gloria Bertoli ◽  
Isabella Castiglioni
Keyword(s):  
Gene Expression ◽  
Gene Expression Analysis ◽  
Distress Syndrome ◽  
Docking Simulation ◽  
Biological Pathways ◽  
Second Step ◽  
Main Protease ◽  
The Stability ◽  
Dynamics Simulations ◽  
Bioinformatic Approach

Abstract BackgroundSARS-CoV-2 coronavirus, an emerging Betacoronavirus, is the causative agent of the severe acute respiratory distress syndrome outbreak in 2019 (COVID-19). Currently, there are neither specific and selective antiviral drugs for the treatment nor vaccines to prevent contagion. Here we propose a bioinformatic approach in order to test in silico the efficacy of existing drugs for COVID-19. ResultsIn the first step of our study we identified, through a gene expression analysis, several drugs that could act on the biological pathways altered in COVID-19. In the second step, we performed a docking simulation in order to test the properties of the identified drugs to target the 3CL main protease of SARS-CoV-2. The drugs that showed higher binding affinity are bardoxolone (-8.78 kcal/ mol), Irinotecan (-8.40 kcal/mol) and Pyrotinib (-8.40 kcal/mol). Molecular dynamics simulations were carried out on the three selected drugs to validate the stability and interactions of the complexes. Among other promising drugs we found also AZD-8055, Olaparib, Tyrphostin AG 879, Topotecan Hydrochloride, MP-412, S-222611, Allitinib, 7-Ethyl-10-Hydroxy-Camptothecin, and Falnidamol. ConclusionsWe suggested some drugs that could efficient in COVID-19. However further studies are suggested to confirm the affinity of these drugs with 3CL main protease of SARS-CoV-2.

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