scholarly journals Insight on the In Silico Study and Biological Activity Assay of Chalcone-Based 1, 5-Benzothiazepines as Potential Inhibitor for Breast Cancer MCF7

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Neni Frimayanti ◽  
◽  
Marzieh Yaeghoobi ◽  
Ihsan Ikhtiarudin ◽  
Dhea Rizki Wannisyah Putri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Free Energy ◽  
Biological Activity ◽  
Molecular Dynamic ◽  
In Silico ◽  
Binding Free Energy ◽  
Crystallographic Structure ◽  
Anticancer Activities ◽  
Adme Prediction ◽  
In Silico Study

In silico study was performed to twelve 1,5-benzothiazepine chalcone derivatives with the protein target from the crystallographic structure modeling of the enzyme tyrosine kinase. The objective of this study is to execute and to estimate the biological activity of chalcone-based 1,5-benzothiazepine derivatives as potential inhibitors for breast cancer MCF7. To get insight into potential anticancer activities, molecular docking, molecular dynamic and ADME prediction were performed. Docking results reported that compound MA9 with binding free energy of -11.2 kcal / mol can interact through hydrogen bonds with amino acids Cys788 on 1T46 protein active site. In addition, the lowest binding free energy conformation indicated its stability during molecular dynamic simulation. MA9 is also shown to have drug likeness properties based on ADME prediction. In order to evaluate the modeling outcomes, MTT assay were performed for some of the most and least promising benzologs (i.e., MA1, MA6, MA8 and MA9). As expected, compound MA9 with the best calculated anticancer properties revealed the best inhibition against MCF7cell line in vitro. Thus, this compound was chosen as the reference for the next stage in the drug design.

In-silico Design, ADMET Screening, MM-GBSA Binding Free Energy of Some Novel Isoxazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer

2019 ◽  
Vol 11 (2) ◽  
pp. 118-128 ◽  
Author(s):  
Rajagopal Kalirajan ◽  
Arumugasamy Pandiselvi ◽  
Byran Gowramma ◽  
Pandiyan Balachandran
Keyword(s):  
Breast Cancer ◽  
Free Energy ◽  
In Silico ◽  
Therapeutic Potential ◽  
Binding Free Energy ◽  
Breast Cancers ◽  
Molecular Docking Study ◽  
In Silico Admet

Background: Human Epidermal development factor Receptor-2 (HER2) is a membrane tyrosine kinase which is overexpressed and gene amplified in human breast cancers. HER2 amplification and overexpression have been linked to important tumor cell proliferation and survival pathways for 20% of instances of breast cancer. 9-aminoacridines are significant DNA-intercalating agents because of their antiproliferative properties. Objective: Some novel isoxazole substituted 9-anilinoacridines(1a-z) were designed by in-silico technique for their HER2 inhibitory activity. Docking investigations of compounds 1a-z are performed against HER2 (PDB id-3PP0) by using Schrodinger suit 2016-2. Methods: Molecular docking study for the designed molecules 1a-z are performed by Glide module, in-silico ADMET screening by QikProp module and binding free energy by Prime-MMGBSA module of Schrodinger suit. The binding affinity of designed molecules 1a-z towards HER2 was chosen based on GLIDE score. Results: Many compounds showed good hydrophobic communications and hydrogen bonding associations to hinder HER2. The compounds 1a-z, aside from 1z have significant Glide scores in the scope of - 4.91 to - 10.59 when compared with the standard Ethacridine (- 4.23) and Tamoxifen (- 3.78). The in-silico ADMET properties are inside the suggested about drug likeness. MM-GBSA binding of the most intense inhibitor is positive. Conclusion: The outcomes reveal that this study provides evidence for the consideration of isoxazole substituted 9-aminoacridine derivatives as potential HER2 inhibitors. The compounds, 1s,x,v,a,j,r with significant Glide scores may produce significant anti breast cancer activity and further in vitro and in vivo investigations may prove their therapeutic potential.

scholarly journals Carvacrol: An In Silico Approach of a Candidate Drug on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR Receptors in the Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Oscar Herrera-Calderon ◽  
Andres F. Yepes-Pérez ◽  
Jorge Quintero-Saumeth ◽  
Juan Pedro Rojas-Armas ◽  
Miriam Palomino-Pacheco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Dynamic ◽  
Cancer Progression ◽  
In Silico ◽  
Computational Study ◽  
Female Rats ◽  
Ligand Docking ◽  
Dynamic Simulations ◽  
In Silico Study ◽  
Egfr Receptors

Carvacrol is a phenol monoterpene found in aromatic plants specially in Lamiaceae family, which has been evaluated in an experimental model of breast cancer. However, any proposed mechanism based on its antitumor effect has not been reported. In our previous study, carvacrol showed a protective effect on 7,12-dimethylbenz[α]anthracene- (DMBA-) induced breast cancer in female rats. The main objective in this research was to evaluate by using in silico study the carvacrol on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR receptors involved in breast cancer progression by docking analysis, molecular dynamic, and drug-likeness evaluation. A multilevel computational study to evaluate the antitumor potential of carvacrol focusing on the main targets involved in the breast cancer was carried out. The in silico study starts with protein-ligand docking of carvacrol followed by ligand pathway calculations, molecular dynamic simulations, and molecular mechanics energies combined with the Poisson–Boltzmann (MM/PBSA) calculation of the free energy of binding for carvacrol. As result, the in silico study led to the identification of carvacrol with strong binding affinity on mTOR receptor. Additionally, in silico drug-likeness index for carvacrol showed a good predicted therapeutic profile of druggability. Our findings suggest that mTOR signaling pathway could be responsible for its preventive effect in the breast cancer.

scholarly journals In silico study on the effects of disulfide bonds in ORF8 of SARS-CoV-2

2021 ◽  
Author(s):  
Yadi Cheng ◽  
Xubiao Peng
Keyword(s):  
Free Energy ◽  
Binding Sites ◽  
In Silico ◽  
Disulfide Bonds ◽  
Immune Modulation ◽  
Binding Free Energy ◽  
Human Leukocyte ◽  
Local Geometry ◽  
Conformational Ensembles ◽  
In Silico Study

The COVID-19 epidemic, caused by virus SARS-CoV-2, has been a pandemic and threatening everyone's health in the past two years. In SARS-CoV-2, the accessory protein ORF8 plays an important role in immune modulation. Here we present an in silico study on the effects of the disulfide bonds in ORF8, including the effects on the structures, the binding sites and free energy when ORF8 binds to the human leukocyte antigen (HLA-A). Using the explicit solvent Molecular Dynamics (MD) simulations, we collect the conformational ensembles on ORF8 with different disulfide bonds reduction schemes. With a new visualization technique on the local geometry, we analyze the effects of the disulfide bonds on the structure of ORF8. We find that the disulfide bonds have large influences on the loop regions of the surface. Moreover, by performing docking between HLA-A and the conformational ensembles of ORF8, we predict the preferred binding sites and find that most of them are little affected by the disulfide bonds. Further, we estimate the binding free energy between HLA-A and ORF8 with different disulfide bonds reductions. In the end, from the comparison with the available experimental results on the epitopes of ORF8, we validated our binding sites prediction. All the above observations may provide inspirations on inhibitor/drug design against ORF8 based on the binding pathway with HLA-A.

scholarly journals Insilico design, ADMET screening, MM-GBSA binding free energy of novel 1,3,4 oxadiazoles linked Schiff bases as PARP-1 inhibitors targeting breast cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Narayan Shridhar Deshpande ◽  
Gowdru Srinivasa Mahendra ◽  
Natasha Naval Aggarwal ◽  
Banylla Felicity Dkhar Gatphoh ◽  
Bistuvalli Chandrashekharappa Revanasiddappa
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Free Energy ◽  
Molecular Docking ◽  
Schiff Bases ◽  
Anticancer Agents ◽  
In Silico ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Parp 1

Abstract Background Poly(ADP-ribose) polymerases (PARPs), a nuclear protein belongs to a new class of drugs, which mainly target tumours with DNA repair defects. They are mainly involved in the multiple cellular processes in addition to the DNA repair process. They act directly on the base excision repair, which is considered as one of the important pathway for cell survival in breast cancer. These belong to the active members of DNA repair assembly and evolved as a key target in the anti-cancer drug discovery. 1,3,4-Oxadiazoles are also well known anticancer agents. Results A novel series of 1,3,4-oxadiazoles linked to Schiff bases (T1-21) were designed and subjected to In-silico analysis against PARP-1 (PDB ID:5DS3) enzyme targeting against breast cancer. Molecular docking study for the designed compounds (T1-21) was performed by In-silico ADMET screening by QikProp module, Glide module and MM-GBSA binding free energy calculations by using Schrodinger suit 2019–2. The PARP-1 enzyme shows the binding affinity against the newly designed molecules (T1-21) based on the glide scores. Compounds T21, T12 showed very good glide score by the molecular docking studies and compared with the standard Tamoxifen. The binding free energies by the MM-GBSA assay were found to be consistent. The pharmacokinetic (ADMET) parameters of all the newly designed compounds were found to be in the acceptable range. Conclusion The selected 1,3,4-oxadiazole-schiff base conjugates seems to be one of the potential source for the further development of anticancer agents against PARP-1 enzyme. The results revealed that some of the compounds T21, T17, T14, T13, T12, T8 with good glide scores showed very significant activity against breast cancer

scholarly journals Structural and Energetic Affinity of Annocatacin B with ND1 Subunit of the Human Mitochondrial Respiratory Complex I as a Potential Inhibitor: An In Silico Comparison Study with the Known Inhibitor Rotenone

Polymers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1840
Author(s):  
Camilo Febres-Molina ◽  
Jorge A. Aguilar-Pineda ◽  
Pamela L. Gamero-Begazo ◽  
Haruna L. Barazorda-Ccahuana ◽  
Diego E. Valencia ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
Complex I ◽  
Binding Free Energy ◽  
Biological Activities ◽  
Experimental Studies ◽  
Respiratory Complex ◽  
Mitochondrial Respiratory Complex ◽  
Respiratory Complex I ◽  
Mitochondrial Respiratory

ND1 subunit possesses the majority of the inhibitor binding domain of the human mitochondrial respiratory complex I. This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, that some metabolites from Annona muricata called acetogenins have important biological activities, such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine mitochondrial respiratory complex I by bis-tetrahydrofurans acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human mitochondrial respiratory complex I. In this work, we evaluate the in silico molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, quantum mechanical optimizations, molecular dynamics simulations and the molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known mitochondrial respiratory complex I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger binding free energy compared to the rotenone complex. Detailed analysis of the binding free energy shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of the mitochondrial respiratory complex I.

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