scholarly journals <i>In-silico</i> Drug Design, ADMET Screening, MM-GBSA Binding Free Energy of Some Chalcone Substituted 9-Anilinoacridines as HER2 Inhibitors for Breast Cancer

2019 ◽  
Vol 7 (1) ◽  
pp. 6 ◽  
Author(s):  
Kalirajan Rajagopal ◽  
Pandiselvi Arumugasamy ◽  
Gowramma Byran
Keyword(s):  
Breast Cancer ◽  
Free Energy ◽  
Drug Design ◽  
In Silico ◽  
Binding Free Energy

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 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 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.

scholarly journals Alchemical Absolute Protein-Ligand Binding Free Energies for Drug Design

2021 ◽  
Author(s):  
Yuriy Khalak ◽  
Gary Tresdern ◽  
Matteo Aldeghi ◽  
Hannah Magdalena Baumann ◽  
David L. Mobley ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Drug Design ◽  
Ligand Binding ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Binding Free Energies

The recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods in drug discovery. Accurately assessing absolute binding free energies, although highly desired, remains...

scholarly journals Three Alkaloids from an Apocynaceae Species, Aspidosperma spruceanum as Antileishmaniasis Agents by In Silico Demo-case Studies

Plants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 983 ◽  
Author(s):  
Diana Morales-Jadán ◽  
José Blanco-Salas ◽  
Trinidad Ruiz-Téllez ◽  
Francisco Centeno
Keyword(s):  
Free Energy ◽  
Active Site ◽  
In Silico ◽  
Binding Free Energy ◽  
New Drugs ◽  
Neglected Tropical Disease ◽  
Physiological Importance ◽  
Promising Tool ◽  
Binding Pockets ◽  
Simulation Results

This paper is focused on demonstrating with a real case that Ethnobotany added to Bioinformatics is a promising tool for new drugs search. It encourages the in silico investigation of “challua kaspi”, a medicinal kichwa Amazonian plant (Aspidosperma spruceanum) against a Neglected Tropical Disease, leishmaniasis. The illness affects over 150 million people especially in subtropical regions, there is no vaccination and conventional treatments are unsatisfactory. In attempts to find potent and safe inhibitors of its etiological agent, Leishmania, we recovered the published traditional knowledge on kichwa antimalarials and selected three A. spruceanum alkaloids, (aspidoalbine, aspidocarpine and tubotaiwine), to evaluate by molecular docking their activity upon five Leishmania targets: DHFR-TS, PTR1, PK, HGPRT and SQS enzymes. Our simulation results suggest that aspidoalbine interacts competitively with the five targets, with a greater affinity for the active site of PTR1 than some physiological ligands. Our virtual data also point to the demonstration of few side effects. The predicted binding free energy has a greater affinity to Leishmania proteins than to their homologous in humans (TS, DHR, PKLR, HGPRT and SQS), and there is no match with binding pockets of physiological importance. Keys for the in silico protocols applied are included in order to offer a standardized method replicable in other cases. Apocynaceae having ethnobotanical use can be virtually tested as molecular antileishmaniasis new drugs.

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