Penapisan Virtual Senyawa–Senyawa dalam Famili Zingiberaeae sebagai Antiinflamasi Menggunakan Protokol EE_COX2_V.1.0

Berbagai penelitian tentang sifat-sifat anti-inflamasi dan anti-kanker dari berbagai senyawa dalam tanaman familia Zingiberaceae telah dilakukan baik secara in vivo maupun in vitro. Enzim yang diinduksi dan diekspresikan pada sel-sel inflamasi dan kanker dianggap sebagai target obat yang ideal untuk menghambat peradangan dan tumorgenesis, salah satunya adalah enzim siklooksigenase-2 (COX-2). Dalam penelitian ini telah dilakukan penapisan virtual senyawa dalam tanaman Kaemferia galanga, Curcuma domestica Val., Zingiber officinale dan Curcuma xanthorrhiza. Tujuan dari penelitian ini adalah untuk mengetahui aktivitas senyawa-senyawa tersebut sebagai penghambat enzim COX-2 secara in-silico. Penelitian ini menggunakan EE_COX2_V.1.0, protokol Structure Based Virtual Screening (SBVS) yang telah divalidasi oleh Mumpuni et al. 2014. Protokol EE_COX2_V.1.0 menggunakan berbagai aplikasi terintegrasi seperti SPORES, PLANTS, BkChem, OpenBabel dan PyMOL. Elusidasi moda ikatan dilakukan terhadap senyawa representatif aktif dan tidak aktif untuk melihat interaksi asam amino dalam binding site senyawa. Berdasarkan skor ChemPLP sebagai hasil dari simulasi docking yang dilakukan pada 27 senyawa, ada 3 senyawa yang berpotensi aktif dalam menghambat COX-2, senyawa tersebut antara lain 2-butil-3- (4-metoksifenil) -2- asam propenoat dengan 6 residu asam amino aktif, 6-shogaol dengan 10 residu asam amino aktif dan desmetoksikurkumin dengan 4 residu asam amino yang aktif.

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MESUAFERRIN A-BIOACTIVE FLAVONOID ISOLATED FROM THE BARK OF MESUA FERREA L. AGAINST PHOSPHOLIPASE A2, CYCLOOXYGENASE AND LIPOXYGENASE: AN IN VITRO, IN VIVO AND IN SILICO APPROACH

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2018v10i2.23576 ◽

2018 ◽

Vol 10 (2) ◽

pp. 102

Author(s):

Krishna Chaithanya K. ◽

Gopalakrishnan V. K. ◽

Zenebe Hagos ◽

Govinda Rao D.

Keyword(s):

Inhibitory Activity ◽

In Silico ◽

Late Phase ◽

Paw Edema ◽

Dual Inhibitor ◽

Metabolizing Enzymes ◽

In Silico Studies ◽

Cox 2

Objective: The main objective of the present study was to evaluate the anti-inflammatory activity of isolated bioactive flavonoid Mesuaferrin-A from the bark of Mesuaferrea L. by in vitro, in vivo and in silico approach.Methods: To evaluate the effect of isolated bioactive flavonoid Mesuaferrin-A on arachidonic acid metabolizing enzymes (PLA2, COX-2 and 5-LOX) using in vitro methods, followed by carrageenan-induced paw edema model by in vivo and to determine the binding orientation and interactions of Mesuaferrin-A onarachidonic acid metabolizing enzymes (PLA2, COX-2 and 5-LOX) crystal proteins using molecular docking (in silico) studies.Results: Mesuaferrin-A exhibited a dose-dependent significant 5-LOX inhibitory and considerable COX-2 inhibitory activity by in vitro, The inhibitory activities of 5-LOX and COX-2 at 100µg/ml were found to be 78.67%, 81.03% with IC50 values of 45.22µg/ml and 35.74µg/ml respectively. Whereas Mesuaferrin-A showed less PLA2 inhibitory activity. Mesuaferrin-A showed 68.34% inhibitory activity at 400 mg/kg body weight at the late phase of carrageenan-induced paw edema, and In silico studies demonstrated that Mesuaferrin-A strongly binds with 5-LOX and COX-2, these strong binding affinity of Mesuaferrin-A on active site amino acids of 5-LOX and COX-2 may be responsible for inhibition of enzyme activity. Mesuaferrin-A showeda comparable 5-LOX and COX-2 inhibition activity with (positive control).Conclusion: It was concluded that Mesuaferrin-A act as 5-LOX and COX dual inhibitor, from the results it was suggests that Mesuaferrin-A, may be an effective preventive and therapeutic approach for patients with inflammatory-related diseases.

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in Silico Docking and Molecular Dynamic Simulation of 3-Dehydroquinate Dehydratase from Mycobacterium Tuberculosis Through Virtual Screening and Pharmacokinetics Studies

10.26434/chemrxiv.12498155.v1 ◽

2020 ◽

Author(s):

Mustafa Alhaji Isa ◽

Muhammad M Ibrahim

Keyword(s):

Mycobacterium Tuberculosis ◽

Virtual Screening ◽

Molecular Dynamic ◽

In Silico ◽

Md Simulation ◽

Binding Energies ◽

In Silico Docking ◽

Pharmacokinetic Properties

The 3-hydroquinate synthase (DHQase) is an enzyme that catalyzes the third step of the shikimate pathway in Mycobacterium tuberculosis (MTB), by converting 3-dehydroquinate into 3-dehydroshikimate. In this study, the novel inhibitors of DHQase from MTB was identified using in silico approach. The crystal structure of DHQase bound to 1,3,4-trihydroxy-5-(3-phenoxypropyl)-cyclohexane-1-carboxylic acid (CA) obtained from the Protein Data Bank (PDB ID: 3N76). The structure prepared through energy minimization and structure optimization. A total of 9699 compounds obtained from Zinc and PubChem databases capable of binding to DHQase and subjected to virtual screening through Lipinski’s rule of five and molecular docking analysis. Eight (8) compounds with good binding energies, ranged between ─8.99 to ─8.39kcal/mol were selected, better than the binding energy of ─4.93kcal/mol for CA and further filtered for pharmacokinetic properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity or ADMET). Five compounds (ZINC14981770, ZINC14741224, ZINC14743698, ZINC13165465, and ZINC8442077) which had desirable pharmacokinetic properties selected for molecular dynamic (MD) simulation and molecular generalized born surface area (MM-GBSA) analyses. The results of the analyses showed that all the compounds formed stable and rigid complexes after the 50ns MD simulation and also had a lower binding as compared to CA. Therefore, these compounds considered as good inhibitors of MTB after in vitro and in vivo validation.”

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Anti-Arthritic and Anti-Inflammatory Potential of Spondias mangifera Extract Fractions: An In Silico, In Vitro and In Vivo Approach

Plants ◽

10.3390/plants10050825 ◽

2021 ◽

Vol 10 (5) ◽

pp. 825

Author(s):

Mohammad Khalid ◽

Mohammed H. Alqarni ◽

Ambreen Shoaib ◽

Muhammad Arif ◽

Ahmed I. Foudah ◽

...

Keyword(s):

Molecular Docking ◽

In Silico ◽

Arthritis Score ◽

Beneficial Effects ◽

Tnf Α ◽

Cox 2 ◽

Anti Inflammatory ◽

Cox 1

The fruits of Spondias mangifera (S. mangifera) have traditionally been used for the management of rheumatism in the northeast region of India. The present study explores the probable anti-arthritis and anti-inflammatory potential of S. mangifera fruit extract’s ethanolic fraction (EtoH-F). To support this study, we first approached the parameters in silico by means of the active constituents of the plant (beta amyrin, beta sitosterol, oleonolic acid and co-crystallised ligands, i.e., SPD-304) via molecular docking on COX-1, COX-2 and TNF-α. Thereafter, the absorption, distribution, metabolism, excretion and toxicity properties were also determined, and finally experimental activity was performed in vitro and in vivo. The in vitro activities of the plant extract fractions were evaluated by means of parameters like 1,1-Diphenyl-2- picrylhydrazyl (DPPH), free radical-reducing potential, albumin denaturation, and protease inhibitory activity. The in vivo activity was evaluated using parameters like COX, TNF-α and IL-6 inhibition assay and arthritis score in Freund Adjuvant (CFA) models at a dose of 400 mg/kg b.w. per day of different fractions (hexane, chloroform, alcoholic). The molecular docking assay was performed on COX-1, COX-2 and TNF-α. The results of in vitro studies showed concentration-dependent reduction in albumin denaturation, protease inhibitors and scavenging activity at 500 µg/mL. Administration of the S. mangifera alcoholic fraction at the abovementioned dose resulted in a significant reduction (p < 0.01) in arthritis score, paw diameters, TNF-α, IL-6 as compared to diseased animals. The docking results showed that residues show a critical binding affinity with TNF-α and act as the TNF-α antagonist. The alcoholic fraction of S. mangifera extract possesses beneficial effects on rheumatoid arthritis as well as anti-inflammatory potential, and can further can be used as a possible agent for novel target-based therapies for the management of arthritis.

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Validating potent anti-inflammatory and anti-rheumatoid properties of Drynaria quercifolia rhizome methanolic extract through in vitro, in vivo, in silico and GC-MS-based profiling

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03265-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Debabrata Modak ◽

Subhashis Paul ◽

Sourav Sarkar ◽

Subarna Thakur ◽

Soumen Bhattacharjee

Keyword(s):

Rheumatoid Arthritis ◽

In Silico ◽

Methanolic Extract ◽

Paw Edema ◽

Active Components ◽

Tnf Α ◽

Cox 2 ◽

Anti Inflammatory

Abstract Background The fronds of Drynaria quercifolia have traditionally been used in rheumatic pain management. The goal of the present study was to validate the potent anti-inflammatory and anti-rheumatoid properties of the methanolic-extract of its rhizome using in vitro, in vivo and in silico strategies. Methods The plant was collected and the methanolic extract was prepared from its rhizome. Protein denaturation test, hypotonicity and heat-induced haemolysis assays were performed in vitro. The in vivo anti-rheumatoid potential was assessed in Freund’s complete adjuvant (FCA)-induced Wistar rat model through inflammatory paw-edema, haematological, biochemical, radiological and histopathological measurements. Moreover, metabolites of methanolic extract were screened by gas chromatography-mass spectrometry (GC-MS) and 3D molecular structures of active components were utilized for in silico docking study using AutoDock. Results In vitro results evinced a significant (p < 0.05) anti-inflammatory activity of the rhizome methanolic extract in a dose-linear response. Further, Drynaria quercifolia rhizome methanolic extract (DME) significantly ameliorated rheumatoid arthritis as indicated by the inhibition of arthritic paw-edema (in millimeter) in the rat rheumatoid arthritis models in both the low (57.71 ± 0.99, p < 0.01) and high dose groups (54.45 ± 1.30, p < 0.001) when compared to arthritic control. Treatment with DME also normalized the haematological (RBC, WBC, platelet counts and hemoglobin contents) and biochemical parameters (total protein, albumin, creatinine and ceruloplasmin) significantly (p < 0.05), which were further supported by histopathological and radiological analyses. Furthermore, GC-MS analysis of DME demonstrated the presence of 47 phytochemical compounds. Compounds like Squalene, Gamma Tocopherol, n-Hexadecanoic acid showed potent inhibition of cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF-α), and interleukin (IL-6) in the docking analysis. Conclusion Results from in vivo and in vitro studies indicated that DME possesses a potent anti-inflammatory and anti-arthritic activity. In silico studies delineated the emergent potent inhibitory effects of several bio-active components on the target inflammatory markers (COX-2, TNF-α and IL-6).

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Virtual Screening for Potential Phytobioactives as Therapeutic Leads to Inhibit NQO1 for Selective Anticancer Therapy

Molecules ◽

10.3390/molecules26226863 ◽

2021 ◽

Vol 26 (22) ◽

pp. 6863

Author(s):

Bhargav Shreevatsa ◽

Chandan Dharmashekara ◽

Vikas Halasumane Swamy ◽

Meghana V. Gowda ◽

Raghu Ram Achar ◽

...

Keyword(s):

Virtual Screening ◽

Binding Site ◽

Anticancer Agents ◽

Substrate Binding ◽

Tumor Burden ◽

Screening Tools ◽

Tumor Promoter ◽

Substrate Binding Site

NAD(P)H:quinone acceptor oxidoreductase-1 (NQO1) is a ubiquitous flavin adenine dinucleotide-dependent flavoprotein that promotes obligatory two-electron reductions of quinones, quinonimines, nitroaromatics, and azo dyes. NQO1 is a multifunctional antioxidant enzyme whose expression and deletion are linked to reduced and increased oxidative stress susceptibilities. NQO1 acts as both a tumor suppressor and tumor promoter; thus, the inhibition of NQO1 results in less tumor burden. In addition, the high expression of NQO1 is associated with a shorter survival time of cancer patients. Inhibiting NQO1 also enables certain anticancer agents to evade the detoxification process. In this study, a series of phytobioactives were screened based on their chemical classes such as coumarins, flavonoids, and triterpenoids for their action on NQO1. The in silico evaluations were conducted using PyRx virtual screening tools, where the flavone compound, Orientin showed a better binding affinity score of −8.18 when compared with standard inhibitor Dicumarol with favorable ADME properties. An MD simulation study found that the Orientin binding to NQO1 away from the substrate-binding site induces a potential conformational change in the substrate-binding site, thereby inhibiting substrate accessibility towards the FAD-binding domain. Furthermore, with this computational approach we are offering a scope for validation of the new therapeutic components for their in vitro and in vivo efficacy against NQO1.

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Ester Prodrugs of Ketoprofen: Synthesis, In Vitro Stability, In Vivo Biological Evaluation and In Silico Comparative Docking Studies Against COX-1 and COX-2

Current Drug Discovery Technologies ◽

10.2174/1570163813666160119092807 ◽

2016 ◽

Vol 13 (1) ◽

pp. 41-57 ◽

Cited By ~ 7

Author(s):

Musa Ahmed ◽

Faizul Azam ◽

Abdul Gbaj ◽

Abdulmottaleb E. Zetrini ◽

Amna S. Abodlal ◽

...

Keyword(s):

In Silico ◽

Docking Studies ◽

Biological Evaluation ◽

Cox 2 ◽

In Vitro Stability ◽

Ester Prodrugs ◽

Cox 1

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In Silico, In Vitro, and In Vivo Analysis of Tanshinone IIA and Cryptotanshinone from Salvia miltiorrhiza as Modulators of Cyclooxygenase-2/mPGES-1/Endothelial Prostaglandin EP3 Pathway

Biomolecules ◽

10.3390/biom12010099 ◽

2022 ◽

Vol 12 (1) ◽

pp. 99

Author(s):

Anella Saviano ◽

Simona De Vita ◽

Maria Giovanna Chini ◽

Noemi Marigliano ◽

Gianluigi Lauro ◽

...

Keyword(s):

In Silico ◽

Ex Vivo ◽

Salvia Miltiorrhiza ◽

Cyclooxygenase 2 ◽

Tanshinone Iia ◽

Prostaglandin E ◽

Platelet Activity ◽

Cox 2

Tanshinone IIA (TIIA) and cryptotanshinone (CRY) from Salvia miltiorrhiza Bunge were investigated for their inhibitory activity against the cyclooxygenase-2 (COX-2)/microsomal prostaglandin E synthase-1 (mPGES-1)/endothelial prostaglandin 3 (EP3) pathway using in silico, in vitro, in vivo, and ex vivo assays. From the analysis of the docking poses, both diterpenoids were able to interact significantly with COX-2, 5-lipoxygenase (5-LO), platelet-activating factor receptor (PAFR), and mPGES-1. This evidence was further corroborated by data obtained from a cell-free assay, where CRY displayed a significant inhibitory potency against mPGES-1 (IC50 = 1.9 ± 0.4 µM) and 5-LO (IC50 = 7.1 µM), while TIIA showed no relevant inhibition of these targets. This was consistent with their activity to increase mice bleeding time (CRY: 2.44 ± 0.13 min, p ≤ 0.001; TIIA: 2.07 ± 0.17 min p ≤ 0.01) and with the capability to modulate mouse clot retraction (CRY: 0.048 ± 0.011 g, p ≤ 0.01; TIIA: 0.068 ± 0.009 g, p ≤ 0.05). For the first time, our results show that TIIA and, in particular, CRY are able to interact significantly with the key proteins involved not only in the onset of inflammation but also in platelet activity (and hyper-reactivity). Future preclinical and clinical investigations, together with this evidence, could provide the scientific basis to consider these compounds as an alternative therapeutic approach for thrombotic- and thromboembolic-based diseases.

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In silico investigations revealed four potential colon cancer drugs from phytochemicals in Zingiber officinale

International Journal of Phytomedicine ◽

10.5138/09750185.1886 ◽

2016 ◽

Vol 8 (3) ◽

pp. 435

Author(s):

Fortunatus Chidolue Ezebuo ◽

Colin B Lukong ◽

Ikemefuna C Uzochukwu ◽

Irene N Okafor

Keyword(s):

Colon Cancer ◽

Binding Site ◽

Ex Vivo ◽

Dihydropyrimidine Dehydrogenase ◽

Zingiber Officinale ◽

Cancer Drug ◽

Cancer Drugs ◽

Tumor Necrosis Factor Ligand

Cancer is a difficult disease to treat, and few effective drugs are available. Hence, it is of great importance to develop effective anti-cancer therapeutic agents with well-defined pharmacokinetic properties. Although, ginger (Zingiber officinale) has a number of proven pharmacological activities, its effect on colon cancer has not received much attention. This study therefore investigated the potential colon cancer drug of compounds found in ginger. Dihydropyrimidine dehydrogenase was modeled using comparative homology modeling and virtual screening was performed locally on a Linux platform using AutoDock Vina®. The results showed that human dihydropyrimidine dehydrogenase is a homolog of pig dihydropyrimidine dehydrogenase. The leads of potential colon cancer drugs were beta-sitosterol, 6-Shogoal, Alloaromadedrene, and Zingiberol. They had similar binding site with levamisole for tumor necrosis factor ligand superfamily member 6 with His 148 and Tyr 192 common at their binding site whereas they had different binding sites from 5-fluorouracil for dihydropyrimidine dehydrogenase. The leads had better bioactivities compared with reference drugs (5-flourouracil and Levamisole) approved clinically for the treatment of colon cancer. In vitro, ex vivo and/or in vivo validations of the leads against colon cancer are recommended.

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in Silico Docking and Molecular Dynamic Simulation of 3-Dehydroquinate Dehydratase from Mycobacterium Tuberculosis Through Virtual Screening and Pharmacokinetics Studies

10.26434/chemrxiv.12498155 ◽

2020 ◽

Author(s):

Mustafa Alhaji Isa ◽

Muhammad M Ibrahim

Keyword(s):

Mycobacterium Tuberculosis ◽

Virtual Screening ◽

Molecular Dynamic ◽

In Silico ◽

Md Simulation ◽

Binding Energies ◽

In Silico Docking ◽

Pharmacokinetic Properties

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Molecular interaction of 4-amino-N’-(benzoyloxy)-N-(2,4- dimethylphenyl)-1,2,5-oxadiazole-3-carboximidamide with the methotrexate binding site of human DHFR, and its implication in rheumatoid arthritis

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i5.20 ◽

2020 ◽

Vol 19 (5) ◽

pp. 1045-1052

Author(s):

Shazi Shakil ◽

Adel M. Abuzenadah ◽

Suzan M. Attar ◽

Omar Fathaldin ◽

Rajaa Al-Raddadi ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Binding Site ◽

Dihydrofolate Reductase ◽

Molecular Interaction ◽

In Silico ◽

Research Work ◽

In Silico Screening ◽

Drug Candidates

Purpose: To identify an improved lead molecule for the human dihydrofolate reductase (DHFR) inhibition that ‘sits’ in the same binding cavity as methotrexate by high throughput computationalscreening.Methods: The 3-D structure of the DHFR binding site was examined using ‘CASTp3.0’. Structure based in silico screening of about 5 million drug candidates housed in the MCULE database was performed. The obtained molecule-hits were ranked in accordance with their VINA scores, made to pass through drug-likeness filters, ΔG cut-off criterion, toxicity-checker and finally ‘zero RO5 criterion’.Results: The ‘top molecule’, namely, 4-amino-N'-(benzoyloxy)-N-(2,4-dimethylphenyl)-1,2,5-oxadiazole- 3-carboximidamide, displayed robust binding with human DHFR through 21 amino acid residues (ΔG = - 9.6 kcal/mol) while 10 of these residues were the same as those displayed by ‘methotrexate binding interactions’. It passed through relevant drug screening filters including the ‘Toxicity Checker’.Conclusion: This research work describes the molecular interaction of human DHFR with an improved lead molecule named, 4-amino- N’-(benzoyloxy)-N-(2,4-dimethylphenyl)-1,2,5-oxadiazole-3- carboximidamide, with a ΔG of -9.6 kcal/mol, thus satisfying adequate ADME features for further in vitro and in vivo validation in the context of rheumatoid arthritis. Keywords: Dihydrofolate reductase, In silico screening, Methotrexate, Rheumatoid arthritis, DHFR

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