Molecular docking, in-silico ADMET screening, MM-GBSA binding free energy of some novel isoxazole substituted 9-amnoacridines as HER2 inhibitors targetting breast cancer

2020 ◽  
Vol 13 (2) ◽  
pp. 155
Author(s):  
Rajagopal Kalirajan ◽  
A. Pandiselvi ◽  
B. Gowramma
Keyword(s):  
Breast Cancer ◽  
Free Energy ◽  
Molecular Docking ◽  
In Silico ◽  
Binding Free Energy ◽  
In Silico Admet

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 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 Quinazolin-4-one derivatives lacking toxicity-producing attributes as glucokinase activators: design, synthesis, molecular docking, and in-silico ADMET prediction

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Saurabh C. Khadse ◽  
Nikhil D. Amnerkar ◽  
Manasi U. Dave ◽  
Deepak K. Lokwani ◽  
Ravindra R. Patil ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Enzyme Assay ◽  
Binding Free Energy ◽  
Docking Studies ◽  
Oral Glucose ◽  
Substitution Pattern ◽  
Glucokinase Activators ◽  
In Silico Admet

Abstract Background A small library of quinazolin-4-one clubbed thiazole acetates/acetamides lacking toxicity-producing functionalities was designed, synthesized, and evaluated for antidiabetic potential as glucokinase activators (GKA). Molecular docking studies were done in the allosteric site of the human glucokinase (PDB ID: 1V4S) enzyme to assess the binding mode and interactions of synthesized hits for best-fit conformations. All the compounds were evaluated by in vitro enzymatic assay for GK activation. Results Data showed that compounds 3 (EC50 = 632 nM) and 4 (EC50 = 516 nM) showed maximum GK activation compared to the standards RO-281675 and piragliatin. Based on the results of the in vitro enzyme assay, docking studies, and substitution pattern, selected compounds were tested for their glucose-lowering effect in vivo by oral glucose tolerance test (OGTT) in normal rats. Compounds 3 (133 mg/dL) and 4 (135 mg/dL) exhibited prominent activity by lowering the glucose level to almost normal, eliciting the results in parallel to enzyme assay and docking studies. Binding free energy, hydrogen bonding, and π–π interactions of most active quinazolin-4-one derivatives 3 and 4 with key amino acid residues of the 1V4S enzyme were studied precisely. Preliminary in-silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction was carried out using SwissADME and PreADMET online software which revealed that all the compounds have the potential to become orally active antidiabetic agents as they obeyed Lipinski's rule of five. Conclusion The results revealed that the designed lead could be significant for the strategic design of safe, effective, and orally bioavailable quinazolinone derivatives as glucokinase activators.

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.

scholarly journals Virtual Screening through Molecular Docking Analysis to Identify Potential Natural Inhibitor(s) of Lyn Tyrosine Kinase- An In-silico Approach

2021 ◽  
pp. 85-105
Author(s):  
Sohini Kulavi ◽  
Soham Banerjee ◽  
Titav Sengupta ◽  
Chandreyi Ghosh ◽  
Moumita Saha ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Tyrosine Kinase ◽  
Bioactive Compounds ◽  
In Silico ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Binding Free Energy ◽  
Pharmacokinetic Analysis ◽  
Lyn Tyrosine Kinase

Breast cancer on becoming one of the leading cancer types, emerged as an important barrier in increasing life expectancy of the overall population. In the current study, some compounds were screened based on literature survey for the identification of natural bioactive compounds as potential inhibitors of Lyn tyrosine kinase. Therefore, a multi-step molecular docking was carried out using AutoDock embedded in the MGL Tools. After initial screening, molecules having a higher docking score and binding free energy compared to Tamoxifen were considered for further assessment. Some already known synthetic lyn tyrosine kinase inhibitor have been used for better understanding of the comparative study. Based on in silico Lipinski filter analysis, toxicity prediction, pharmacokinetic analysis, four compounds were proposed to be promising inhibitors of Lyn tyrosine kinase. Furthermore, the binding interactions of all proposed inhibitors of Lyn showed strong ligand efficiency in terms of energy score obtained with the help of molecular modelling analyses. Hence, the proposed compounds out of which three are bioactive compounds might be taken forward as potential next-generation Lyn kinase inhibitors for managing Lyn associated breast cancer after experimental authentication.

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