Pyrazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer – An In-Silico Approach

2021 ◽  
Vol 13 ◽  
Author(s):  
Kalirajan Rajagopal ◽  
Vulsi Bodhya Sri ◽  
Gowramma Byran ◽  
Swaminathan Gomathi
Keyword(s):  
Breast Cancer ◽  
Binding Affinity ◽  
In Silico ◽  
Antitumor Agents ◽  
Docking Studies ◽  
Tyrosine Kinase Receptor ◽  
Population Total ◽  
Female Population ◽  
In Silico Admet ◽  
In Silico Studies

Background: Breast cancer is one of the malignant tumours which mainly affect the female population. Total 20% of the cases of breast cancer are due to overexpression of Human epidermal growth factor receptor-2 (HER2), which is the dominant tyrosine kinase receptor. In general, 9-anilinoacridine derivatives play an important role as antitumor agents due to their DNA-intercalating properties. Objective: Some novel 9-anilinoacridines substituted with pyrazole moiety(1a-z) were designed, and their HER2enzyme (PDB id-3PP0) inhibition activity was evaluated by molecular docking studies using the Glide module of Schrodinger suite 2019-4. Methods: Glide module of the Schrodinger suite was used to perform docking studies, qikprop module was used for in-silico ADMET screening, and the Prime-MM-GBSA module was used for free binding energy calculations. Using GLIDE scoring functions, we can determine the binding affinity of ligands (1a-z) towards HER2. Results: The inhibitory activity of ligands against HER2 was mainly due to the strong hydrophobic and hydrogen bonding interactions. Almost all the compounds 1a-z have a good binding affinity with Glide scores in the range of -4.9 to -9.75 compared to the standard drugs CK0403(-4.105) and Tamoxifen (-3.78). From the results of in-silico ADMET properties, most of the compounds fall within the recommended values. MM-GBSA binding calculations of the most potent inhibitors are more favourable. Conclusion: The results of in-silico studies provide strong evidence for the consideration of valuable ligands in pyrazole substituted 9-anilinoacridines as potential HER2 inhibitors, and the compounds, 1v,s,r,d, a,o with significant Glide scores may produce significant anti-breast cancer activity for further development.

scholarly journals Anti-cancer and Antimicrobial Activity, In-Silico ADME and Docking Studies of Biphenyl Pyrazoline Derivatives

2020 ◽  
Vol 11 (1) ◽  
pp. 8266-8282
Keyword(s):  
Breast Cancer ◽  
Antimicrobial Activity ◽  
Binding Affinity ◽  
In Silico ◽  
Chemical Properties ◽  
Cancer Cell Line ◽  
Docking Studies ◽  
Spectral Studies ◽  
Compound 21 ◽  
Affinity Score

The present study deals with the multicomponent Michal addition reaction of xenyl chalcone (10-17) reacting with hydrazine hydrate in the presence of ethane carboxylic acid. It afforded new pyrazoline compounds. The propane pyrazoline derivatives (18-25) skeleton structure was confirmed by spectral studies like Fourier-Transform Infrared spectroscopy, 1H NMR, 13C NMR, and CHN analysis. The adsorption, distribution, metabolism, and excretion (ADME) properties of the synthesized molecules were investigated. The results obtained in-silico demonstrated that these molecules could be considered as orally active drug candidates due to their physical and chemical properties. The compounds (18-25) were subjected to docking prediction studies by protein (1UAG) and breast cancer protein (1OQA). While Comparing with the drug ciprofloxacin, among the series of eight compounds (18-25), compound 19, 20, and 24 have the best binding affinity score (-8.5 kcal/mol). We have selected only the compound 21 (4-Cl (electronegativity group)) compound for MTT assay of breast cancer cell line studies because it has the best binding affinity score in the binding study of the compound with 1OQA protein. Synthesized pyrazoline compound (18-25) also obeys the Lipinski rule of five and other criteria of drug-likeness properties. Among the synthesized pyrazoline compound (18-25), especially compound 21 (electronegativity group (4-Cl) has the best drug-likeness property and has a value of 7.16. Furthermore, antimicrobial activity of these compounds has been evaluated against five microbial strains, and from this result, some of the newly synthesized compounds exhibit good activity.

scholarly journals Synthesis, Spectral Characterization, in Vitro and in Silico Studies of Benzodioxin Pyrazoline derivatives

2020 ◽  
Vol 11 (2) ◽  
pp. 9126-9138
Keyword(s):  
Breast Cancer ◽  
In Silico ◽  
Oral Absorption ◽  
Docking Studies ◽  
In Vitro Studies ◽  
Bacterial Protein ◽  
Online Tools ◽  
In Silico Studies ◽  
Theoretical Results

The present study deals with the in silico and in vitro studies of DBDP derivatives, which is formed from the Michal-addition reaction of DihydroBenzo[b]Dioxin Chalcone Derivatives(DBDD) with hydrazine hydrate and carboxyethane. The DBDD were synthesized via Claisen condensation between substituted aldehyde and 1,4-(benzodioxan-6-yl)-methyl ketone. The newly arrived compounds were characterized by IR and NMR spectra. The structurally confirmed synthesized compounds were screened against 1UAG microbial protein, 1OQA cancer protein using auto dock software, and ADME properties also found by using (in silico) Swissadme and Molinspiration online tools. All the newly arrived DBDP compounds have passed the acceptable values of ADME (drug-likeness), medicinal property, and lead likeness in ADME prediction. Compound DBDP-9 scored better values in drug-likeness. It obeys the five basic rules (Lipinski, Ghose, Verber, Egan, and Muegge) of medicinal chemistry property, passed the PAINS, Brenk filters with 0 violation, and also have better lead likeness value. All the other compounds in this series also passed the above-mentioned properties with 1 or 2 violations only present in PAINS and Brenk filter. This theoretical results incitement to performed docking and in vitro studies of the DBDP derivatives. Docking studies results that the good I.S averse to 1 UAG bacterial protein than standard drugs and also give impact values in the docking against 1OQA breast cancer protein. Overall observation from the above studies, DBDP-9 has a maximum oral absorption value 91.36% with 0 violation alert in drug-likeness, medicinal property, and pharmacokinetics filter. DBDP-4 has a good I.S (-8.8), DBDP-2 has 4 numbers of HBI as standard, and all the DBDP 1-9 compounds have higher I.S than the standard and also have impact I.S against 1OQA breast cancer protein.

Activity of Thiazine substituted 9-anilinoacridines against Corona virus (COVID19): An In-silico approach

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 482-490
Author(s):  
Kalirajan Rajagopal ◽  
Potlapati Varakumar ◽  
Baliwada Aparna ◽  
Vulsi Bodhya Sri ◽  
Gowramma Byran ◽  
...  
Keyword(s):  
In Silico ◽  
Binding Free Energy ◽  
Viral Disease ◽  
Docking Studies ◽  
Binding Modes ◽  
Main Protease ◽  
In Silico Admet ◽  
In Silico Studies ◽  
Life Threatening ◽  
Similar Mode

Coronavirus Disease 2019 (COVID-19), a life-threatening viral disease affected first in Wuhan, China, and quickly spread to more than 200 countries in the world in the year 2020. So many scientists are trying to discover novel drugs and vaccines for coronavirus and treatment for COVID-19. In the present article, in-silico studies have been performed to explore the binding modes of Thiazine substituted 9-anilinoacridines (1a-z) against SARS CoV 2 main protease (PDB id - 5R82) targeting the coronavirus using Schrodinger suit 2019-4. The molecular docking studies are performed by Glide module, in-silico ADMET screening was performed by Qik prop module, and the binding free energy of ligands was calculated using PRIME MM-GB/SA module of Schrodinger suite 2019-4, Maestro 21.2 version. From the in-silico results, Thiazine substituted 9-anilinoacridines like 1m, 1j, 1s and 1b are significantly active against SARS CoV 2 main protease with Glide score more than -5.4 when compared with the currently recommended drug for COVID19, Hydroxychloroquine (G score -5.47). The docking results of the Thiazine substituted 9-anilinoacridines exhibited similar mode of interactions with COVID19 and the residues GLN19, THR24, THR25, THR26, LEU27, HIE41, SER46, MET49, ASN142, GLN143, HIE164, MET165, ASP187, ARG188 and GLN189, play a crucial role in binding with ligands.

In Silico ADMET and Docking Studies of Thiazolidinedione-acetic-acid Hybrids as Antidiabetics with Cardioprotection

2020 ◽  
Vol 17 (12) ◽  
pp. 1475-1484
Author(s):  
Deepanwita Maji ◽  
Subir Samanta ◽  
Vaishali M. Patil
Keyword(s):  
Acetic Acid ◽  
Amino Acid ◽  
Side Effects ◽  
In Silico ◽  
Methyl Esters ◽  
Antioxidant Properties ◽  
Docking Studies ◽  
Single Amino Acid ◽  
In Silico Admet ◽  
In Silico Studies

Background: Type-2-diabetes mellitus is associated with many side effects affecting vital body organs, especially heart. Thiazolidinediones are potent antidiabetics. Studies have proven that amino-acids and peptides promote glucose transport, have antioxidant properties, and fewer side effects, thus we designed hybrids by combining amino-acid esters and peptide esters with 2, 4 thiazolidinedione acetic acid moiety which can act as antidiabetic agent with cardioprotection properties. Methodology: In vitro ADME, toxicity, and docking studies were performed using Qikprop3.1.OSIRIS, PROTOX (Prediction of Rodent Oral Toxicity), and FlexX 2.1.3, respectively. Results: All the designed molecules belong to three sub-series, i.e. 2, 4-dioxothiazolidine-5-acetic acid single amino acid hybrid methyl esters, 2, 4-dioxothiazolidine-5-acetic acid dipeptide hybrid methyl esters and 2, 4-dioxothiazolidine-5-acetic acid tripeptide hybrid methyl esters. All molecules were non-toxic. SSMA2, SSMA14, SSMA49, and SSDM50 showed good docking scores in 2PRG and 2UV4, respectively. Conclusion: The selected in silico studies helped to design hybrids with less toxicity, target specificity with dual activity as potential anti-diabetic and cardioprotective agents.

In-silico Studies of Isolated Phytoalkaloid Against Lipoxygenase: Study Based on Possible Correlation

2018 ◽  
Vol 21 (3) ◽  
pp. 215-221
Author(s):  
Haroon Khan ◽  
Muhammad Zafar ◽  
Helena Den-Haan ◽  
Horacio Perez-Sanchez ◽  
Mohammad Amjad Kamal
Keyword(s):  
In Silico ◽  
Docking Studies ◽  
In Vivo Studies ◽  
In Vitro Assays ◽  
Chronic Obstructive ◽  
Lipoxygenase Inhibitors ◽  
Lipoxygenase Inhibition ◽  
In Silico Studies

Aim and Objective: Lipoxygenase (LOX) enzymes play an important role in the pathophysiology of several inflammatory and allergic diseases including bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis and chronic obstructive pulmonary disease. Inhibitors of the LOX are believed to be an ideal approach in the treatment of diseases caused by its over-expression. In this regard, several synthetic and natural agents are under investigation worldwide. Alkaloids are the most thoroughly investigated class of natural compounds with outstanding past in clinically useful drugs. In this article, we have discussed various alkaloids of plant origin that have already shown lipoxygenase inhibition in-vitro with possible correlation in in silico studies. Materials and Methods: Molecular docking studies were performed using MOE (Molecular Operating Environment) software. Among the ten reported LOX alkaloids inhibitors, derived from plant, compounds 4, 2, 3 and 1 showed excellent docking scores and receptor sensitivity. Result and Conclusion: These compounds already exhibited in vitro lipoxygenase inhibition and the MOE results strongly correlated with the experimental results. On the basis of these in vitro assays and computer aided results, we suggest that these compounds need further detail in vivo studies and clinical trial for the discovery of new more effective and safe lipoxygenase inhibitors. In conclusion, these results might be useful in the design of new and potential lipoxygenase (LOX) inhibitors.

Enzymatic Textile Dyes Decolorization by In vitro and In silico Studies

2019 ◽  
Vol 13 (4) ◽  
pp. 268-276
Author(s):  
Sridevi Ayla ◽  
Monika Kallubai ◽  
Suvarnalatha Devi Pallipati ◽  
Golla Narasimha
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Docking Studies ◽  
Textile Dyes ◽  
Crude Enzyme ◽  
Eastern Ghats ◽  
Textile Dye ◽  
Phanerochaete Sordida ◽  
Molecular Docking Studies ◽  
In Silico Studies

Background:Laccase, a multicopper oxidoreductase (EC: 1.10.3.2), is a widely used enzyme in bioremediation of textile dye effluents. Fungal Laccase is preferably used as a remediating agent in the treatment and transformation of toxic organic pollutants. In this study, crude laccase from a basidiomycetes fungus, Phanerochaete sordida, was able to decolorize azo, antroquinone and indigoid dyes. In addition, interactions between dyes and enzyme were analysed using molecular docking studies.Methods:In this work, a white rot basidiomycete’s fungus, Phanerochaete sordida, was selected from forest soil isolates of Eastern Ghats, and Tirumala and lignolytic enzymes production was assayed after 7 days of incubation. The crude enzyme was checked for decolourisation of various synthetic textile dyes (Vat Brown, Acid Blue, Indigo, Reactive Blue and Reactive Black). Molecular docking studies were done using Autodock-4.2 to understand the interactions between dyes and enzymes.Results:Highest decolourisation efficiency was achieved with the crude enzyme in case of vat brown whereas the lowest decolourisation efficiency was achieved in Reactive blue decolourisation. Similar results were observed in their binding affinity with lignin peroxidase of Phanerochaete chrysosporium through molecular docking approach.Conclusion:Thus, experimental results and subsequent in silico validation involving an advanced remediation approach would be useful to reduce time and cost in other similar experiments.

Synthesis, investigation of biological effects and in silico studies of new benzimidazole derivatives as aromatase inhibitors

2020 ◽  
Vol 75 (9-10) ◽  
pp. 353-362
Author(s):  
Begüm Nurpelin Sağlık ◽  
Ahmet Mücahit Şen ◽  
Asaf Evrim Evren ◽  
Ulviye Acar Çevik ◽  
Derya Osmaniye ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
In Silico ◽  
Biological Effects ◽  
Docking Studies ◽  
Benzimidazole Derivatives ◽  
Binding Modes ◽  
Reference Drug ◽  
In Silico Studies ◽  
New Compounds ◽  
Mcf 7

AbstractInhibition of aromatase enzymes is very important in the prevention of estrogen-related diseases and the regulation of estrogen levels. Aromatase enzyme is involved in the final stage of the biosynthesis of estrogen, in the conversion of androgens to estrogen. The development of new compounds for the inhibition of aromatase enzymes is an important area for medicinal chemists in this respect. In the present study, new benzimidazole derivatives have been designed and synthesized which have reported anticancer activity in the literature. Their anticancer activity was evaluated against human A549 and MCF-7 cell lines by MTT assay. In the series, concerning MCF-7 cell line, the most potent compounds were the 4-benzylpiperidine derivatives 2c, 2g, and 2k with IC50 values of 0.032 ± 0.001, 0.024 ± 0.001, and 0.035 ± 0.001 µM, respectively, compared to the reference drug cisplatin (IC50 = 0.021 ± 0.001 µM). Then, these compounds were subject to further in silico aromatase enzyme inhibition assays to determine the possible binding modes and interactions underlying their activity. Thanks to molecular docking studies, the effectiveness of these compounds against aromatase enzyme could be simulated. Consequently, it has been found that these compounds can be settled very properly to the active site of the aromatase enzyme.

Design, Synthesis, In Vitro and In Silico Studies of Some Novel Triazoles as Anticancer Agents for Breast Cancer

2021 ◽  
pp. 131198
Author(s):  
Derya Osmaniye ◽  
Begum Nurpelin Saglik ◽  
Serkan Levent ◽  
Sinem Ilgın ◽  
Yusuf Ozkay ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Anticancer Agents ◽  
In Silico ◽  
Design Synthesis ◽  
In Silico Studies

scholarly journals IN SILICO STUDIES OF THE SECONDARY METABOLITES OF SOLANUM TORVUM SW. FOR THEIR ANTIASTHMATIC ACTIVITY

2017 ◽  
Vol 9 (4) ◽  
pp. 38
Author(s):  
Soorya R. ◽  
Dhamodaran P. ◽  
Rajesh Kumar R. ◽  
Duraisamy B.
Keyword(s):  
Methyl Ester ◽  
Secondary Metabolites ◽  
Ethyl Ester ◽  
In Silico ◽  
Methanolic Extract ◽  
Acid Ethyl Ester ◽  
Docking Studies ◽  
Receptor Protein ◽  
Solanum Torvum ◽  
In Silico Studies

Objective: Solanum torvum Sw., Family: Solanaceae, commonly known as Turkey Berry is used by the traditional tribes for the treatment of cold, cough, tuberculosis, hepatotoxicity, cancer, etc. The action of the plant towards the treatment of these diseases has been proven except for asthma. The present study is to prove the antiasthmatic activity of methanolic extract and the secondary metabolites of Solanum torvum Sw using in silico docking studies in compare to reference standard Dexamethasone, a synthetic cortisone derivative.Methods: The GC-MS analysis of the dried methanolic extract of the dried fruits of Solanum torvum Sw. and the total saponin fraction has been carried out to know the important moieties that are responsible for the antiasthmatic activity.Results: The results from the docking studies showed that the compounds Cholesta-5,7,9-(11)-trien-3-ol,4,4-dimethyl, (3á); Lanosta-7,9-(11),20-triene-3α, 18-diol, diacetate and Cholestan-26-oic acid,3,7,12,24-tetrakis (acetyloxy), methyl ester, (3à,5á,7à,12à) were found to have significant scores of-6.8,-6.9 and-6.9 respectively towards Glucocorticoid receptor protein (Gr), (PDB id: 4UDC) which is very similar to the affinity of the standard (-7.1). These compounds passed the drug-likeness test. A modification in the structure can be brought, which makes the compounds more potent. The compounds 9, 12-Octadecadienoic acid, ethyl ester; Hexadecanoic acid, ethyl ester; 9-Octadecenoic acid (Z), methyl ester; Oxacycloheptadec-8-en-2-one, (8Z) have passed the Blood Brain Barrier (BBB) filter of the drug-likeness test.Conclusion: The antiasthmatic activity of the drug may be due to the similarity with the structure of Dexamethasone. Further research can be carried out in order to improve the clinical significance of these extracts and its metabolites.

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