In silico Discovery of Resveratrol Analogues as Potential Agents in Treatment of Metabolic Disorders

Background: Resveratrol was demonstrated to act as partial agonist of PPAR-γ receptor, which opens up the possibility for its use in the treatment of metabolic disorders. Considering the poor bioavailability of resveratrol, particularly due to its low aqueous solubility, we aimed to identify analogues of resveratrol with improved pharmacokinetic properties and higher binding affinities towards PPAR-γ. Methods: 3D structures of resveratrol and its analogues were retrieved from ZINC database, while PPAR-γ structure was obtained from Protein Data Bank. Docking studies were performed using Molegro Virtual Docker software. Molecular descriptors relevant to pharmacokinetics were calculated from ligand structures using VolSurf+ software. Results: Using structural similarity search method, 56 analogues of resveratrol were identified and subjected to docking analyses. Binding energies were ranged from -136.69 to -90.89 kcal/mol, with 16 analogues having higher affinities towards PPAR-γ in comparison to resveratrol. From the calculated values of SOLY descriptor, 23 studied compounds were shown to be more soluble in water than resveratrol. However, only two tetrahydroxy stilbene derivatives, piceatannol and oxyresveratrol, had both better solubility and affinity towards PPAR-γ. These compounds also had more favorable ADME profile, since they were shown to be more metabolically stable and wider distributed in body than resveratrol. Conclusion: Piceatannol and oxyresveratrol should be considered as potential lead compounds for further drug development. Although experimental validation of obtained in silico results is required, this work can be considered as a step toward the discovery of new natural and safe drugs in treatment of metabolic disorders.

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Comprehensive Virtual Screening of the Antiviral Potentialities of Marine Polycyclic Guanidine Alkaloids against SARS-CoV-2 (COVID-19)

Biomolecules ◽

10.3390/biom11030460 ◽

2021 ◽

Vol 11 (3) ◽

pp. 460

Author(s):

Amr El-Demerdash ◽

Ahmed M. Metwaly ◽

Afnan Hassan ◽

Tarek Mohamed Abd El-Aziz ◽

Eslam B. Elkaeed ◽

...

Keyword(s):

In Silico ◽

Active Sites ◽

Specific Treatment ◽

Aqueous Solubility ◽

Maximum Tolerated Dose ◽

Binding Energies ◽

Log P ◽

Binding Affinities ◽

Structural Protein ◽

Guanidine Alkaloids

The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine alkaloids encouraged us to run a comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2, which we investigated. The investigated proteins are COVID-19 main protease (Mpro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (5) and crambescidin 826 (13) has been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = −8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = −6.49 kcal/mol), and nsp10 (ΔG = −9.06 kcal/mol). Compound 13 showed promising binding affinities against Mpro (ΔG = −7.99 kcal/mol), spike glycoproteins (ΔG = −6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = −8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The correlation of c Log P with free binding energies has been calculated. Furthermore, the SAR of the active compounds has been clarified. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies were carried out in silico for the 15 compounds; most examined compounds showed optimal to good range levels of ADMET aqueous solubility, intestinal absorption and being unable to pass blood brain barrier (BBB), non-inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD50, rat maximum tolerated dose, rat oral LD50, and rat chronic lowest observed adverse effect level (LOAEL)). All compounds showed expected low toxicity against the tested models. Molecular dynamic (MD) simulations were also carried out to confirm the stable binding interactions of the most promising compounds, 5 and 13, with their targets. In conclusion, the examined 15 alkaloids specially 5 and 13 showed promising docking, ADMET, toxicity and MD results which open the door for further investigations for them against SARS-CoV-2.

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Homology Modelling and Molecular Docking Studies of Selected Substituted Benzo[d]imidazol-1-yl)methyl)benzimidamide Scaffolds on Plasmodium falciparum Adenylosuccinate Lyase Receptor

Bioinformatics and Biology Insights ◽

10.1177/1177932219865533 ◽

2019 ◽

Vol 13 ◽

pp. 117793221986553 ◽

Cited By ~ 1

Author(s):

Gbolahan O Oduselu ◽

Olayinka O Ajani ◽

Yvonne U Ajamma ◽

Benedikt Brors ◽

Ezekiel Adebiyi

Keyword(s):

Plasmodium Falciparum ◽

Molecular Docking ◽

In Silico ◽

Homology Modelling ◽

3D Structure ◽

Docking Studies ◽

Binding Energies ◽

Benzimidazole Derivatives ◽

Adenylosuccinate Lyase ◽

In Silico Admet

Plasmodium falciparum adenylosuccinate lyase ( PfADSL) is an important enzyme in purine metabolism. Although several benzimidazole derivatives have been commercially developed into drugs, the template design as inhibitor against PfADSL has not been fully explored. This study aims to model the 3-dimensional (3D) structure of PfADSL, design and predict in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) of 8 substituted benzo[ d]imidazol-1-yl)methyl)benzimidamide compounds as well as predict the potential interaction modes and binding affinities of the designed ligands with the modelled PfADSL. PfADSL 3D structure was modelled using SWISS-MODEL, whereas the compounds were designed using ChemDraw Professional. ADMET predictions were done using OSIRIS Property Explorer and Swiss ADME, whereas molecular docking was done with AutoDock Tools. All designed compounds exhibited good in silico ADMET properties, hence can be considered safe for drug development. Binding energies ranged from −6.85 to −8.75 kcal/mol. Thus, they could be further synthesised and developed into active commercial antimalarial drugs.

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Rigid and flexible docking studies on PPAR-γ agonists: key interactions for a better antihyperglycemic activity and in silico pharmacodynamic activity versus experimental in vivo activity

Medicinal Chemistry Research ◽

10.1007/s00044-011-9548-x ◽

2011 ◽

Vol 21 (5) ◽

pp. 624-633 ◽

Cited By ~ 3

Author(s):

B. R. Prashantha Kumar ◽

S. Sopna ◽

Jenson Verghese ◽

Bijoy Desai ◽

M. J. Nanjan

Keyword(s):

In Silico ◽

Docking Studies ◽

Flexible Docking ◽

Antihyperglycemic Activity ◽

Ppar Γ

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A Molecular Docking Study of N-Ferrocenylmethylnitroanilines as Potential Anticancer Drugs

International Journal of Pharmacology Phytochemistry and Ethnomedicine ◽

10.18052/www.scipress.com/ijppe.2.5 ◽

2016 ◽

Vol 2 ◽

pp. 5-12 ◽

Cited By ~ 2

Author(s):

Touhami Lanez ◽

Elhafnaoui Lanez

Keyword(s):

Escherichia Coli ◽

Molecular Docking ◽

Protein Structure ◽

Dna Gyrase ◽

Data Bank ◽

Docking Study ◽

Docking Studies ◽

Molecular Docking Study ◽

Molegro Virtual Docker ◽

Gyrase A

In the present study, the interaction of the protein structure of Escherichia coli DNA Gyrase-A (EcGyr-A) extracted from protein data bank (PDB Code: 1AB4) with ligands N-ferrocenylmethyl-2-nitroaniline (2FMNA), N-ferrocenylmethyl-3-nitroaniline (3FMNA) and N-ferrocenylmethyl-4-nitroaniline (4FMNA) were investigated by performing docking studies using the Molegro Virtual Docker (MVD) software. The results obtained showed that the best poses which is derived from MolDock score for Escherichia coli DNA Gyrase-A were respectively equal to-92.0111, -96.0866 and-95.6808 with reranking score equal to-40.9575, -73.4476 and-73.6423. Calculations revealed that 3FMNA react strongly with EcGyr-A followed by 4-FMNA and 2-FMNA.

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In silico study examining new phenylpropanoids targets with antidepressant activity

Current Drug Targets ◽

10.2174/1389450121666200902171838 ◽

2020 ◽

Vol 21 ◽

Author(s):

Luciana Scotti ◽

Poliane da Silva Calixto ◽

Mirian G. S. Stiebbe Salvadori ◽

Reinaldo Nóbrega de Almeida ◽

Mayara dos Santos Maia ◽

...

Keyword(s):

In Silico ◽

Late Onset ◽

Clinical Psychopharmacology ◽

Three Dimensional ◽

Public Health Problem ◽

Antidepressant Activity ◽

Docking Studies ◽

Dimensional Structure ◽

Molegro Virtual Docker ◽

Stereochemical Quality

Background: Natural products, such as phenylpropanoids, which are found in essential oils derived from aromatic plants, have been explored during non-clinical psychopharmacology studies, to discover new molecules with relevant pharmacological activities in the central nervous system, especially antidepressant and anxiolytic activities. Major depressive disorder is a highly debilitating psychiatric disorder and is considered to be a disabling public health problem, worldwide, as a primary factor associated with suicide. Current clinically administered antidepressants have late-onset therapeutic actions, are associated with several side effects, and clinical studies have reported that some patients do not respond well to treatment or reach complete remission. Objective: To review important new targets for antidepressant activity and to select phenylpropanoids with antidepressant activity, using Molegro Virtual Docker and Ossis Data Warris, and to verify substances with more promising antidepressant activity. Results and Conclusion: We conducted an in silico molecular modeling study, based on homology, to determine the three-dimensional structure the 5-hydroxytryptamine 2A receptor (5-HT2AR), then performed molecular docking studies and examined the predisposition for cytotoxicity risk among identified molecules. We obtained a model for 5-HT2AR homology, with satisfactory results, indicating the good stereochemical quality of the model. The phenylpropanoid 4- allyl-2,6-dimethoxyphenol showed the lowest binding energy for 5-HT2AR, with results relevant to the L-arginine/nitric oxide (NO)/cGMP pathway, and showed no toxicity within the parameters of mutagenicity, carcinogenicity, reproductive system toxicity, and skin-tissue irritability, when evaluated in silico; therefore, this molecule can be considered promising for the investigation of antidepressant activity.

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Novel Cinnamic Acid Derivatives as Potential PPARδ Agonists for Metabolic Syndrome: Design, Synthesis, Evaluation and Docking Studies

Current Drug Discovery Technologies ◽

10.2174/1570163816666190314124543 ◽

2020 ◽

Vol 17 (3) ◽

pp. 338-347

Author(s):

Ajay Chauhan ◽

Ajmer S. Grewal ◽

Deepti Pandita ◽

Viney Lather

Keyword(s):

Cinnamic Acid ◽

In Silico ◽

Metabolic Disorders ◽

Docking Studies ◽

Antidiabetic Activity ◽

Oral Glucose ◽

Peroxisome Proliferator ◽

Cinnamic Acid Derivatives ◽

In Silico Docking ◽

Study Results

Background: Peroxisome proliferator-activated receptor (PPAR) δ is expressed universally in the entire tissues, particularly in those concerned with the lipid metabolism. PPAR δ stimulation alters body’s energy fuel preference to fat from glucose and shows up as an emerging pharmacological target for the treatment of metabolic disorders. Methods: A new series of cinnamic acid derivatives was synthesized and evaluated for the antidiabetic and antiinflammatory activities in the animal models followed by in silico docking studies to determine the binding interactions for the best fit conformations in the binding site of the PPARδ protein. Results: Amongst the synthesized molecules, compound 3 showed higher antidiabetic activity in oral glucose tolerance test and compound 1 showed higher antiinflammatory activity in the carrageenan induced rat paw oedema method. The in vivo study results were supported by the similar in silico molecular docking results. Most of the synthesized derivatives showed drug likeness as depicted via Lipinski’s rule of 5. Conclusion: These molecules can serve as the early hit molecules for the discovery of safe, effective and bioavailable PPARδ agonists for the potential treatment of various metabolic disorders.

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Targeting Omp-A Protein of Acinetobacter Baumannii with the Bio-Active Compounds from Azadirachta Indica - an in-silico Approach

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i48b33290 ◽

2021 ◽

pp. 323-334

Author(s):

R. Nandita ◽

A. S. Smiline Girija ◽

P. Sankar Ganesh ◽

J. Vijayashree Priyadharsini

Keyword(s):

Crystal Structure ◽

Acinetobacter Baumannii ◽

Azadirachta Indica ◽

In Silico ◽

3D Structure ◽

Data Bank ◽

Binding Energies ◽

Active Compounds ◽

Discovery Studio ◽

Ompa Protein

Background: Acinetobacter baumannii is a gram negative bacterium which is typically short, round, coccobacillus and was named after the bacteriologist Paul Baumann. It is an emerging dental pathogen since it acquires drug resistance and expression of several virulence genes. It is an opportunistic pathogen in humans, affecting people with compromised immune systems. Acinetobacter baumannii is an arising nosocomial microorganism causing serious complications because of the propensity of its multi-drug resistant property. Aim: The aim of the present study was to target omp-A protein of Acinetobacter baumannii with the bio active compounds from Azadirachta indica an in-silico approach. Materials and Methods: The crystal structure of ompA protein was obtained from the PDB protein data bank. The structures of the bio-active derivatives of A. indica were obtained from the chemsketch software. The generated 3D structures were then optimised. Auto Dock instrument was utilized for docking investigation to interpret the affinity between bio-compounds of A. indica against ompA protein of A. baumannii. Results: The 3D crystal structure of OmpA-like domain from A.baumannii was retrieved from PDB database and its PDB ID was 3TD3 – A chain. 3D Structure of OmpA visualization using Biovia-Discovery studio visualizer. The 2D structure of compounds from Azadirachta indica was drawn using ACD chemsketch and saved in MDL-mol format and converted to PDB format using open babel converter. The final docked structures for the drug ligand interactions were assessed for their binding energies and hydrogen bonds. Conclusion: The present study had achieved the anti-biofilm inhibitory effect of imidazole-2-carboxylic acid from A. indica exhibiting a great interaction between activity with ompA utilizing computational investigation.

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POTENSI SENYAWA AKTIF BUNGA, KULIT DAUN DAN GETAH Aloe barbadensis Miller. TERHADAP PENGHAMBATAN ENZIM TYROSINASE

Pharmacoscript ◽

10.36423/pharmacoscript.v1i1.106 ◽

2019 ◽

Vol 1 (1) ◽

Author(s):

Nur Aji

Keyword(s):

Ferulic Acid ◽

Protein Data Bank ◽

In Silico ◽

Sinapic Acid ◽

Aloe Vera ◽

Data Bank ◽

Gentisic Acid ◽

Aloe Barbadensis ◽

Molegro Virtual Docker

Pada penelitian ini dilakukan simulasi penambatan molekul senyawa-senyawa aktif pada bunga, kulit daun dan getah tanaman Aloe barbadensis Miller . Simulasi ini bertujuan untuk memprediksi interaksi antara senyawa ligan uji dan protein yang menyebabkan terganggunya pembentukan melanin melalui interaksi kompetitif dengan enzim tirosinase. Simulasi penambatan molekul dilakukan menggunakan program Molegro Virtual Docker 6.0 dan prediksi permeabilitas dan sensitisasi kulit dengan pkCSM. Sebagai reseptor target digunakan struktur 3D protein 5M8P (tirosinase) dan ligan referensi TYR_516 (L-tirosin) yang diunduh dari Protein Data Bank. Posisi penambatan dilakukan pada koordinat yang sama dengan posisi ligan referensi yang sudah tertambat sebelumnya dan tervalidasi. Dari hasil simulasi diketahui bahwa dari 32 senyawa aktif dalam kulit daun, bunga dan getah aloe vera secara in silico terdapat tujuh senyawa yang potensial yang memiliki efek penghambatan tirosinase yaitu Aloesin, Cafeic Acid, Ferulic Acid, Galic Acid, Gentisic Acid, Protocathecuic Acid dan Sinapic Acid sedangkan berdasarkan energi interaksi potensi terbesar adalah Caffeic Acid.Kata kunci :Aloe barbadensis, Molegro, Enzim, Tirosinase, pkCSM.

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In Silico Exploration of Potential Natural Inhibitors against SARS-Cov-2 nsp10

Molecules ◽

10.3390/molecules26206151 ◽

2021 ◽

Vol 26 (20) ◽

pp. 6151

Author(s):

Ibrahim H. Eissa ◽

Mohamed M. Khalifa ◽

Eslam B. Elkaeed ◽

Elsayed E. Hafez ◽

Aisha A. Alsfouk ◽

...

Keyword(s):

In Silico ◽

Density Functional ◽

Nonstructural Protein ◽

Structural Similarity ◽

Docking Studies ◽

Similarity Analysis ◽

Selection Methods ◽

Functional Theory ◽

Adenosyl Methionine ◽

Natural Inhibitors

In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.

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Comprehensive Virtual Screening of the Antiviral Potentialities of Marine Polycyclic Guanidine Alkaloids against SARS-CoV-2 (Covid-19)

10.26434/chemrxiv.13335899.v1 ◽

2020 ◽

Author(s):

Amr El-Demerdash ◽

Ahmed M. Metwaly ◽

Tarek Mohamed Abd El-Aziz4 ◽

Ibrahim H. Eissa ◽

James D. Stockand

Keyword(s):

In Silico ◽

Active Sites ◽

Aqueous Solubility ◽

Maximum Tolerated Dose ◽

Vital Role ◽

Binding Energies ◽

Binding Affinities ◽

Structural Protein ◽

Fatty Acid Chain ◽

Guanidine Alkaloids

A comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2 has been investigated. The investigated proteins are COVID-19 main protease (Mpro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (5) and crambescidin 826 (13) have been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = -8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = -6.49 kcal/mol), and nsp10 (ΔG = -9.06 kcal/mol). Compound 13 showed promising binding affinities against Mpro (ΔG = -7.99 kcal/mol), spike glycoproteins (ΔG = -6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = -8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The ADMET studies were carried out in silico for the 15 compounds, all examined compounds (except compounds 8 and 15) have low or very low BBB penetration levels. Compounds 1, 5, 6, 9, 12 and 13 showed optimal range levels of ADMET aqueous solubility. Compounds 1, 2, 3, 8, and 15 were predicted to have good intestinal absorption levels, while compounds 4, 7, 9, 10, and 14 showed moderate absorption levels. All examined alkaloids (except the bicyclic compound 8) were predicted not to be inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD50, rat maximum tolerated dose, rat oral LD50 and rat chronic LOAEL). All compounds showed expected low toxicity against the tested models.

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