scholarly journals APPLICATION OF IN SILICO STUDIES TARGETING TELOMERIC G-QUADRUPLEX COMPLEX BY PERYLENE DIIMIDES FOR ANTICANCER THERAPY

2018 ◽  
Vol 11 ◽  
Author(s):  
Hemalatha Cn, ◽  
Vijey Aanandhi M
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Data Bank ◽  
Anticancer Therapy ◽  
Standard Drug ◽  
Perylene Diimides ◽  
Discovery Studio ◽  
In Silico Studies ◽  
G Quadruplex ◽  
Ic50 Values

Objective: Telomerase enzyme which is expressed in detectable levels and its mechanism was that it increases the length when it binds to telomeres. This eventually leads to extension of lifespan of cells and also makes an attractive target for cancer therapy. Perylene diimides bind to telomerase with duplex genomic DNA, and these G-quadruplex ligands are of responsible for binding affinity with respective proteins. Based on the IC50 values of perylene diimides, QSAR has been studied out and the results are elaborated in preliminary research works. From the results of QSAR, the selected perylene ligands are selected for docking choosing telomerase as a target/protein. From the results of in silico studies, new compounds are designed and synthesized accordingly. Now, the objective of the study was to dock the final synthesized compounds with the telomerase protein to study regarding the pKi value using G-quadruplex ligand database (G4LDB). The docked results are visualized using Discovery Studio Visualizer 4.1. The results are compared with the standard N,N’-bis-(2-(1-piperidino)ethyl)-3,4,9,10-perylene tetracarboxylic acid diimide (PIPER) drug and these compounds will be effective for anticancer therapy.Methods: The study was to investigate the docking results of synthesized perylene compounds with the results from G4LDB and visualized by Discovery Studio 4.1 Visualizer. The telomerase proteins selected for the study were extracted from Protein Data Bank, and the proteins selected for the study are 3SC8 and 3CE5. Among the compounds (R1, R2, R3, and R4) screened in G-Quadruplex Ligand Database, compound R3 shows better binding affinity with good pKi value as well the interactions with the protein and ligand show better affinity with the targets and these are compared with the standard drug PIPER drug.Results: Compound R3 possesses the best binding affinity with the target 3CE5 and 3SC8 which shows that the compound will be effective for anticancer therapy.

scholarly journals Homology modeling of actin protein in Leishmania donovani and in silico prediction of active drugs

2020 ◽  
Vol 2 ◽  
pp. 52-57
Author(s):  
Dimpal Rani Bansal ◽  
Hanumanthrao Chandershekar Patil ◽  
Rajesh Kumari Patil
Keyword(s):  
Homology Modeling ◽  
Binding Affinity ◽  
In Silico ◽  
Structure Prediction ◽  
Leishmania Donovani ◽  
Secondary Structure Prediction ◽  
3D Structure ◽  
Data Bank ◽  
Discovery Studio ◽  
Actin Protein

Objectives: Leishmaniasis is a disease caused by leishmania parasite which is genus of trypanosome protozoa. Leishmania donovani promastigote inhibits biogenesis of phagolysosome due to the accumulation of periphagosomal F-actin. This inhibition of phagosome maturation gives favorable environment for differentiation of promastigote-to-amastigote and causes disease progression. L. donovani actin (LdACT) has been found to have unconventional biochemical behavior due to the different amino acid region in its sequence suggesting that it must have a three-dimensional (3D) structure different from eukaryotic actins making it a more specific for predication of antileishmanial drugs which is main objective of this study. Material and Methods: For carrying out this study, protein sequence was retrieved from the database SWISSPROT, analyzed by BIOEDIT software followed by primary and secondary structure prediction by PROTPARAM and SOPMA. A 3D structure of same was constructed by homology modeling using the yeast actin-human gelsolin segment 1 complex (protein data bank [PDB] ID:1yag) as a template with the help of Swiss model. The final model obtained was further accessed by PROCHECK and VERIFY 3D software which ensured the reliability of the model. This model of actin protein was further used for screening different chemical compounds with high binding affinity by GOLD and DISCOVERY STUDIO. Results: The results give information about the some inhibitors having highest binding affinity to the actin protein. Conclusion: This study will be useful for the development of pharmacophore models for in silico predication of active drugs as a part of antileishmanial drug therapy.

scholarly journals Antimalarial Flavonoid-Glycoside from Acacia pennata with Inhibitory Potential Against PfDHFR-TS: An In-silico Study

2021 ◽  
Vol 12 (4) ◽  
pp. 4871-4887
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Enzyme Inhibitor ◽  
Docking Simulation ◽  
Flavonoid Glycoside ◽  
Flavonoid Glycosides ◽  
Discovery Studio ◽  
Antimalarial Agents ◽  
In Silico Studies ◽  
Inhibitory Potential

Drug resistance, toxicity, and adverse effects of current antimalarial drugs have mandated the need to search for newer antimalarial agents. The present study aims to identify promising flavonoid-glycosides (FGs) from Acacia pennata as possible antimalarial agents effective against PfDHFR-TS (PDB ID: 3DGA) by in-silico studies. The co-crystal inhibitor (RJ1) of PfDHFR-TS was used as the reference standard compound. A compound library of 17 FGs reported to be isolated from A. pennata was prepared and subjected to molecular docking simulation studies. PyRx 0.8 and AutoDock Vina revealed Pinocembrin-7-O-β-D-glucopyranoside (FG17) as the best PfDHFR-TS inhibitor with a binding affinity of -10.4 kcal/mol and -10.8 kcal/mol, respectively. In both methods, FG17 has a better binding affinity than the co-crystal inhibitor, RJ1 (-7.9 kcal/mol). The docking protocols were validated by RMSD calculation with Discovery Studio Visualizer software (2020). FG17 interacted with amino acids ALA16, LEU40, SER167, GLY41, GLY44, MET55, PHE58, ILE112, LEU119, GLY166, and TYR170 at the active binding site of PfDHFR-TS. Further, FG17 was computed as a non-toxic, bioavailable, synthetically accessible compound and a better enzyme inhibitor than RJ1. Hence, we conclude that FG17 may be used as a lead scaffold to design antimalarial agents against PfDHFR-TS in the future.

scholarly journals In silico studies of selected xanthophylls as potential candidates against SARS-CoV-2 targeting main protease (Mpro) and papain-like protease (PLpro)

2021 ◽  
Vol 67 (2) ◽  
pp. 1-8
Author(s):  
Tomasz M. Karpiński ◽  
Marek Kwaśniewski ◽  
Marcin Ożarowski ◽  
Rahat Alam
Keyword(s):  
Binding Energy ◽  
Active Site ◽  
In Silico ◽  
Active Sites ◽  
Data Bank ◽  
Pharmacokinetic Parameters ◽  
Discovery Studio ◽  
Main Protease ◽  
In Silico Studies ◽  
Potential Inhibitors

Summary Introduction: The main protease (Mpro) and the papain-like protease (PLpro) are essential for the replication of SARS-CoV-2. Both proteases can be targets for drugs acting against SARS-CoV-2. Objective: This paper aims to investigate the in silico activity of nine xanthophylls as inhibitors of Mpro and PLpro. Methods: The structures of Mpro (PDB-ID: 6LU7) and PLpro (PDB-ID: 6W9C) were obtained from RCSB Protein Data Bank and developed with BIOVIA Discovery Studio. Active sites of proteins were performed using CASTp. For docking the PyRx was used. Pharmacokinetic parameters of ADMET were evaluated using SwissADME and pkCSM. Results: β-cryptoxanthin exhibited the highest binding energy: –7.4 kcal/mol in the active site of Mpro. In PLpro active site, the highest binding energy had canthaxanthin of –9.4 kcal/mol, astaxanthin –9.3 kcal/mol, flavoxanthin –9.2 kcal/mol and violaxanthin –9.2 kcal/mol. ADMET studies presented lower toxicity of xanthophylls in comparison to ritonavir and ivermectin. Conclusion: Our findings suggest that xanthophylls can be used as potential inhibitors against SARS-CoV-2 main protease and papain-like protease.

Synthesis and In-silico Studies of C-4 Substituted Coumarin Analogues as Anticancer Agents

2020 ◽  
Vol 16 ◽  
Author(s):  
Jyoti Dandriyal ◽  
Kamalpreet Kaur ◽  
Vikas Jaitak
Keyword(s):  
Anticancer Agents ◽  
Active Site ◽  
In Silico ◽  
Oral Absorption ◽  
In Vivo Studies ◽  
Conventional Heating ◽  
Microwave Assisted Synthesis ◽  
Standard Drug ◽  
In Silico Studies ◽  
Adme Properties

Background: Coumarin is a fused ring system and possesses enormous capability of targeting various receptors participating in cancer pathway. Coumarin and its derivatives were found to exhibit very rare toxicity and other side effects. It has been found its immense anticancer potential depends on the nature of group present and its pattern of substitution on the basic nucleus. Objectives: Synthesis of C-4 substituted coumarin derivatives and to study their molecular interactions with ERα for anticancer activity for Breast Cancer. Method: C-4 substituted coumarins analogues (1-10) have been synthesized using conventional heating and microwave irradiation. Using Schrodinger software molecular modeling studies were carried out and ADME properties of the compounds were predicted. Results: All the synthesized compounds have shown better G-Score (-6.87 to -8.43 kcal/mol) as compared to the standard drug tamoxifen (-5.28kcal/mol) and auraptene (-3.89kcal/mol). Molecular docking suggests that all compounds fit in the active site of protein as they have the same hydrophobic pocket as standard drug tamoxifen, and have an acceptable range of ADME properties. Conclusion: Microwave-assisted synthesis showed better results as compared to conventional heating. In-silico studies revealed that all the compounds befit in the active site of protein. ADME properties showed that all compounds are in allowable limits for human oral absorption. In future, there is a possibility of in-vitro and in-vivo studies of the synthesized compounds.

scholarly journals Synthesis, in silico studies and antibacterial activity of some novel 2-substituted benzimidazole derivatives

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Ramakrishna Chintakunta ◽  
Geethavani Meka
Keyword(s):  
Antibacterial Activity ◽  
Melting Point ◽  
In Silico ◽  
Software Tool ◽  
Benzimidazole Derivatives ◽  
Recrystallization Process ◽  
Standard Drug ◽  
In Silico Studies ◽  
Drug Synthesis ◽  
Percentage Absorption

Abstract Background The o-phenylenediamine is a versatile starting material for several compounds. Synthesized o-phenylenediamine and amino acids (glycine, alanine, aspartic acid, and l-proline) undergo condensation via Phillips reaction. The synthesized compound showed the promising antibacterial activity of Bacillus subtilis and Pseudomonas aeruginosa at the concentration of 100, 50, 25, 12.5, 6.25, 3.12, 1.6, 0.8, 0.4, and 0.2 μg/ml. Ciprofloxacin was used as standard drug. Synthesis of benzimidazole derivatives was carried out and purified by recrystallization process using ethanol. Substituted derivatives were characterized by melting point, TLC and spectroscopic methods include FT-IR and 1H-NMR. Results In silico studies were adopted for synthetic derivatives by Molinspiration, ChemDraw, and online software tool. Minimum inhibitory concentration (MIC) values of B. subtilis and P. aeruginosa were reported, and benzimidazole ligands and Molinspiration scores were generated and listed. Conclusion The more negative values indicate a higher binding affinity. The generated ligand observations can be visualized. Physical constants of synthesized derivates such as solubility and melting point were determined. Bioactivity scores were noted for different derivatives and predicted percentage absorption in the gut. The antibacterial activity was performed using the MIC method (aerobic).

scholarly journals Synthesis, Antileishmanial Activity and in silico Studies of Aminoguanidine Hydrazones (AGH) and Thiosemicarbazones (TSC) Against Leishmania chagasi Amastigotes

2021 ◽  
Vol 17 ◽  
Author(s):  
Thiago M. de Aquino ◽  
Paulo H. B. França ◽  
Érica E. E. S. Rodrigues ◽  
Igor J. S. Nascimento ◽  
Paulo F. S. Santos-Júnior ◽  
...  
Keyword(s):  
In Silico ◽  
Biological Activities ◽  
Leishmania Species ◽  
Antileishmanial Activity ◽  
Trypanothione Reductase ◽  
Aromatic Substituent ◽  
In Silico Studies ◽  
Ic50 Values ◽  
The Impact

Background: Leishmaniasis is a worldwide health problem, highly endemic in developing countries. Among the four main clinical forms of the disease, visceral leishmaniasis is the most severe, fatal in 95% of cases. The undesired side-effects from first-line chemotherapy and the reported drug resistance search for effective drugs that can replace or supplement those currently used an urgent need. Aminoguanidine hydrazones (AGH's) have been explored for exhibiting a diverse spectrum of biological activities, in particular the antileishmanial activity of MGBG. The bioisosteres thiosemicarbazones (TSC's) offer a similar biological activity diversity, including antiprotozoal effects against Leishmania species and Trypanosoma cruzi. Objective: Considering the impact of leishmaniasis worldwide, this work aimed to design, synthesize, and perform a screening upon L. chagasi amastigotes and for the cytotoxicity of the small "in-house" library of both AGH and TSC derivatives and their structurally-related compounds. Method: A set of AGH's (3-7), TSC's (9, 10), and semicarbazones (11) were initially synthesized. Subsequently, different semi-constrained analogs were designed and also prepared, including thiazolidines (12), dihydrothiazines (13), imidazolines (15), pyrimidines (16, 18) azines (19, 20), and benzotriazepinones (23-25). All intermediates and target compounds were obtained with satisfactory yields and exhibited spectral data consistent with their structures. All final compounds were evaluated against L. chagasi amastigotes and J774.A1 cell line. Molecular docking was performed towards trypanothione reductase using GOLD® software. Result: The AGH's 3i, 4a, and 5d, and the TSC's 9i, 9k, and 9o were selected as valuable hits. These compounds presented antileishmanial activity compared with pentamidine, showing IC50 values ranged from 0.6 to 7.27 μM, maximal effects up to 55.3%, and satisfactory SI values (ranged from 11 to 87). On the other hand, most of the resulting semi-constrained analogs were found cytotoxic or presented reduced antileishmanial activity. In general, TSC class is more promising than its isosteric AGH analogs, and the beneficial aromatic substituent effects are not similar in both series. In silico studies have suggested that these hits are capable of inhibiting the trypanothione reductase from the amastigote forms. Conclusion: The promising antileishmanial activity of three AGH’s and three TSC’s was characterized. These compounds presented antileishmanial activity compared with PTD, showing IC50 values ranged from 0.6 to 7.27 μM, and satisfactory SI values. Further pharmacological assays involving other Leishmania strains are under progress, which will help to choose the best hits for in vivo experiments.

In silico studies of bacterial derived fatty acid as a potential inhibitor of 1FGE and 1BQO

2021 ◽  
Vol 16 (12) ◽  
pp. 119-124
Author(s):  
S. Syed Chandini ◽  
Sairam Mantri
Keyword(s):  
Ligand Binding ◽  
Stearic Acid ◽  
In Silico ◽  
In Vivo Studies ◽  
Binding Interaction ◽  
Standard Drug ◽  
Synthetic Drugs ◽  
Potential Inhibitor ◽  
In Silico Studies

Thrombomodulin (TM) and matrix metalloproteinase (MMPs) are the major factors that are responsible for lung cancer. Hence, the identification of novel compounds inhibiting TM and MMPs is the challenging task for the scientists. Even though synthetic drugs were developed, their toxicity and offtarget limit their usage. The current study aims to investigate the molecular simulations for bacterial derived stearic acid to estimate the in silico anticancer activity against TM and MMPs protein as target compounds and the findings were correlated with the standard drug vorinostat. Using Lamarckian genetic algorithm, the TM and MMPs were energy minimized and docked with stearic acid and vorinostat using auto dock 4.2 and visualized in PyMol software. Protein and ligand binding analysis revealed that stearic acid interacts with the amino acids of MMPs residues of PHE83, SER212, ALA213 and ASN214. It interacts with the TMs with two amino acid residues i.e. CYS407 and GLU408. Hence, compared to vorinostat, stearic acid shows a higher binding affinity towards MMPs and slightly lower affinity towards TM proteinase. We conclude that the computational analysis of ligand binding interaction of stearic acid suggests that it could be a potential inhibitor of matrix metallo proteinase and is effective against thrombomodulin and can be considered as an anticancer agent by in vivo studies.

scholarly journals In-silico Molecular Docking and ADME/Pharmacokinetic Prediction Studies of Some Novel Carboxamide Derivatives as Anti-tubercular Agents

2020 ◽  
Vol 3 (4) ◽  
pp. 989-1000
Author(s):  
Mustapha Abdullahi ◽  
Shola Elijah Adeniji
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
In Silico ◽  
Density Functional ◽  
Docking Simulation ◽  
Basis Set ◽  
Hybrid Functional ◽  
Standard Drug

AbstractMolecular docking simulation of thirty-five (35) molecules of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamide (IPA) with Mycobacterium tuberculosis target (DNA gyrase) was carried out so as to evaluate their theoretical binding affinities. The chemical structure of the molecules was accurately drawn using ChemDraw Ultra software, then optimized at density functional theory (DFT) using Becke’s three-parameter Lee–Yang–Parr hybrid functional (B3LYP/6-311**) basis set in a vacuum of Spartan 14 software. Subsequently, the docking operation was carried out using PyRx virtual screening software. Molecule 35 (M35) with the highest binding affinity of − 7.2 kcal/mol was selected as the lead molecule for structural modification which led to the development of four (4) newly hypothetical molecules D1, D2, D3 and D4. In addition, the D4 molecule with the highest binding affinity value of − 9.4 kcal/mol formed more H-bond interactions signifying better orientation of the ligand in the binding site compared to M35 and isoniazid standard drug. In-silico ADME and drug-likeness prediction of the molecules showed good pharmacokinetic properties having high gastrointestinal absorption, orally bioavailable, and less toxic. The outcome of the present research strengthens the relevance of these compounds as promising lead candidates for the treatment of multidrug-resistant tuberculosis which could help the medicinal chemists and pharmaceutical professionals in further designing and synthesis of more potent drug candidates. Moreover, the research also encouraged the in vivo and in vitro evaluation study for the proposed designed compounds to validate the computational findings.

scholarly journals In Silico Studies on Fungal Metabolite against Skin Cancer Protein (4,5-Diarylisoxazole HSP90 Chaperone)

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Saravanakumar Kandasamy ◽  
Sunil Kumar Sahu ◽  
Kathiresan Kandasamy
Keyword(s):  
Methyl Ester ◽  
Skin Cancer ◽  
Secondary Metabolites ◽  
In Silico ◽  
Octadecenoic Acid ◽  
Mangrove Sediment ◽  
Heptadecanoic Acid ◽  
Standard Drug ◽  
Methyl Methyl ◽  
In Silico Studies

This work was to find out the dominant secondary metabolites derived from the fungus Trichoderma and to test them against skin cancer protein. The metabolites were extracted in 80% methanol from the fungal biomass of Trichoderma isolated from mangrove sediment. The crude methanol extract was purified and analysed for the secondary metabolites by GC-MS. Three predominant compounds (heptadecanoic acid, 16 methyl-, methyl ester; 9,12-octadecadienoic acid; cis-9-octadecenoic acid) identified in the extracts were screened against the skin cancer protein (Hsp90) by in-silico docking method. Of the compounds, heptadecanoic acid, 16 methyl, methyl ester was the most potent having the docking score of  Kcal/mol. This value was better than the standard drug “dyclonine”. This work recommends the heptadecanoic acid, 16 methyl, methyl ester for further in vitro and in vivo studies towards its development as anticancer drug.

scholarly journals Docking studies, synthesis, characterization, and cytotoxicity activity of new bis-chalcones derivatives

2021 ◽  
Vol 8 (4) ◽  
pp. 4294-4305
Author(s):  
Mohammad Murwih Alidmat ◽  
Melati Khairuddean ◽  
Salizawati Muhamad Salhimi ◽  
Mohammad Al-Amin
Keyword(s):  
Inhibitory Concentration ◽  
Data Bank ◽  
2D Nmr ◽  
Docking Studies ◽  
Standard Drug ◽  
Discovery Studio ◽  
Cytotoxicity Activity ◽  
Diphenyl Tetrazolium Bromide ◽  
New Compounds ◽  
Mcf 7

Introduction: A bis-chalcones were prepared by the reaction of terephthalaldehyde with 3-acetyl-2,5-dichlorothiophene or 3-acetyl- 5-chlorothiophene and reaction cyclo ketone derivatives with phenyl aldehyde derivatives in good yields. Methods: The molecular docking studies were conducted using the Discovery Studio (DSv4.5) and MG. Tools installed in Window 10. The cancer receptor (3ERT) was downloaded from the protein data bank (PDB). All new compounds were characterized by IR, 1H-NMR, 13C-NMR, 2D-NMR, and CHN elemental analysis. The anticancer activity of the synthesized compounds was determined using MTT (3-(4, 5- dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) reduction assay against MCF-7 cells, and then the minimum inhibitory concentration (IC50) was determined with the reference of the standard drug tamoxifen. Results: The results showed that compound 6 showed more potent activity in inhibiting growth on both types of MCF-7 compared to reference tamoxifen.    

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