Antagonistic Mechanism of Chalcone Derivatives Against Human Estrogen Alpha of Breast Cancer Using Molecular Dynamic Simulation

2’,4’-dihydroxy-6-methoxy-3,5-dimethylchalcone (ChalcEA) that isolated from Eugenia aquea Burm f. leaves has a potential anticancer activity against human breast adenocarcinoma cell lines (MCF-7). The objective of this study was to modify ChalcEA to increase its activity as an antagonist of breast cancer with computational simulation approach. A molecular docking simulation was done against the modification structure of ChalcEA with Autodock4 to determine binding interaction between ChalcEA and hERα receptor agonists (PDB ID 1g50). Subsequently, the structure with the smallest bond energy value from the docking result was simulated using molecular dynamics to see its stability within a certain time. The results of molecular docking showed that ChalcEA modification which has a phenol group and pyrazole (MK2) had the free binding energy (ΔG) with a value of -10.2 kcal/mol and bonding hydrogen with GLU353 and ARG394, while estradiol had a value of ΔG=-10.7 kcal/mol. Based on molecular dynamics results, the determination of binding energy was gained using MMPBSA (Molecular Mechanics Poisson-Boltzmann and Surface Area) calculation methods. The MK2 has the better affinity than estradiol with a value of ΔGTotal=-45.10 kcal/mol, while estradiol was amounted to -40.86 kcal /mol. This study suggests that the MK2 might be potential as an antagonist to the hERα of breast cancer.

Download Full-text

Molecular Dynamics Simulation Estrogen Receptor Alpha againts Andrographolide as Anti Breast Cancer

Indonesian Journal of Pharmaceutical Science and Technology ◽

10.24198/ijpst.v6i2.18168 ◽

2019 ◽

Vol 6 (2) ◽

pp. 65

Author(s):

Doni Dermawan ◽

Riyadi Sumirtanurdin ◽

Deti Dewantisari

Keyword(s):

Breast Cancer ◽

Molecular Dynamics ◽

Estrogen Receptor ◽

Molecular Docking ◽

Molecular Dynamics Simulation ◽

Estrogen Receptor Alpha ◽

Docking Simulation ◽

Dynamics Simulation ◽

Receptor Alpha ◽

A Value

Breast cancer is the most common cancer suffered by women with 1.67 million new cases in the world by 2012 with a mortality rate of 12.9%. Tamoxifen is a standard therapy for breast cancer but can cause endometrial and thromboembolic cancer. Andrografolid is an active compound from Andrographis paniculata which has antiproliferation activity of MCF-7 breast cancer cells with IC50 was 61.11 μM. The purpose of this study was to design andrographolide modification structures as human estrogen receptor alpha (hER-α) antagonists. Molecular docking simulation results showed that the andrographolide and AND5 (best andrographolide derivative) have free binding energy (ΔG) values were -9.65 kcal/mol and -12.43 kcal/mol, respectively, and hydrogen bonds were formed with Gly521, Asp351, and Met343. The ΔG value of ANDS was lower than tamoxifen (-11.40 kcal/mol). Pharmacophore modeling results showed that andrographolide and AND5 had a high pharmacophore-fit value of 46.39% and 63.47%, respectively. Molecular dynamics simulation using MM-PBSA calculation method, showed that the hERα-AND5 system has a value of ΔGTOTAL = -50.52 kcal/mol compared to the hERα-estradiol system as an agonist with a value of ∆GTOTAL = -40.86 kcal/mol . These results suggested that AND5 has better affinity for hERα compared to estradiol so that AND5 is a very promising anti breast cancer agent.Keywords: Andrographolide, molecular dynamics, breast cancer, molecular docking, estrogen receptor alpha

Download Full-text

Quantitative structure-activity relationship model, molecular docking simulation and computational design of some novel compounds against DNA gyrase receptor.

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200625142447 ◽

2020 ◽

Vol 16 ◽

Author(s):

Shola Elijah Adeniji

Keyword(s):

Biological Activity ◽

Molecular Docking ◽

Binding Energy ◽

Biological Activities ◽

Docking Simulation ◽

Dna Gyrase ◽

Computational Design ◽

Multi Drug Resistance ◽

Drug Candidate ◽

Standard Drug

Introduction: Mycobacterium tuberculosis has instigated a serious challenge toward the effective treatment of tuberculosis. The reoccurrence of the resistant strains of the disease to accessible drugs/medications has mandate for the development of more effective anti-tubercular agents with efficient activities. Time expended and costs in discovering and synthesizing new hypothetical drugs with improved biological activity have been a major challenge toward the treatment of multi-drug resistance strain M. tuberculosis (TB). Meanwhile, to solve the problem stated, a new approach i.e. QSAR which establish connection between novel drugs with a better biological against M. tuberculosis is adopted. Methods: The anti-tubercular model established in this study to forecast the biological activities of some anti-tubercular compounds selected and to design new hypothetical drugs is subjective to the molecular descriptors; MATS7s, SM1_DzZ, SpMin4_Bhv, TDB3v and RDF70v. Ligand-receptor interactions between quinoline derivatives and the receptor (DNA gyrase) was carried out using molecular docking technique by employing the PyRx virtual screening software and discovery studio visualizer software. Furthermore, docking study indicates that compounds 20 of the derivatives with promising biological activity have the utmost binding energy of -17.79 kcal/mol. Results: Meanwhile, the interaction of the standard drug; isoniazid with the target enzyme was observed with the binding energy -14.6 kcal/mol which was significantly lesser than the binding energy of the ligand (compound 20).Therefore, compound 20 served as a template structure to designed compounds with more efficient activities. Among the compounds designed; compounds 20p was observed with better anti-tubercular activities with more prominent binding affinities of -24.3kcal/mol. Conclusion: The presumption of this research aid the medicinal chemists and pharmacist to design and synthesis a novel drug candidate against the tuberculosis. Moreover, in-vitro and in-vivo test could be carried out to validate the computational results.

Download Full-text

Synthesis, In-vitro and Docking Analysis of C-3 substituted Coumarin Analogues as Anticancer Agents C-3 Substituted Coumarins as Anticancer Agents

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200120114641 ◽

2020 ◽

Vol 16 ◽

Author(s):

Anuradha Thakur ◽

Kamalpreet Kaur ◽

Praveen Sharma ◽

Ramit Singla ◽

Sandeep Singh ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Anticancer Agents ◽

Proliferative Activity ◽

Binding Interaction ◽

Diverse Range ◽

Mcf 7 ◽

Substituted Coumarins

Background: Breast cancer (BC) is a leading cause of cancer-related deaths in women next to skin cancer. Estrogen receptors (ERs) play an important role in the progression of BC. Current anticancer agents have several drawbacks such as serious side effects and the emergence of resistance to chemotherapeutic drugs. As coumarins possess minimum side effect along with multi-drug reversal activity, it has a tremendous ability to regulate a diverse range of cellular pathways that can be explored for selective anticancer activity. Objectives: Synthesis and evaluation of new coumarin analogues for anti-proliferative activity on human breast cancer cell line MCF-7 along with exploration of binding interaction of the compounds for ER-α target protein by molecular docking. Method: In this study, the anti-proliferative activity of C-3 substituted coumarins analogues (1-17) has been evaluated against estrogen receptor-positive MCF-7 breast cancer cell lines. Molecular interactions and ADME study of the compounds were analyzed by using Schrodinger software. Results: Among the synthesized analogues 12 and 13 show good antiproliferative activity with IC50 values 1and 1.3 µM respectively. Molecular docking suggests a remarkable binding pose of all the seventeen compounds. Compounds 12 and 13 were found to exhibit dock score of -4.10 kcal/mol and -4.38 kcal/mol respectively. Conclusion: Compounds 12 and 13 showed the highest activity followed by 1 and 5. ADME properties of all compounds were in the acceptable range. The active compounds can be taken for lead optimization and mechanistic interventions for their in vivo study in the future.

Download Full-text

Study of Endogen Substrates, Drug Substrates and Inhibitors Binding Conformations on MRP4 and Its Variants by Molecular Docking and Molecular Dynamics

Molecules ◽

10.3390/molecules26041051 ◽

2021 ◽

Vol 26 (4) ◽

pp. 1051

Author(s):

Edgardo Becerra ◽

Giovanny Aguilera-Durán ◽

Laura Berumen ◽

Antonio Romo-Mancillas ◽

Guadalupe García-Alcocer

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Binding Energy ◽

Binding Site ◽

Binding Sites ◽

Adenosine Monophosphate ◽

Competitive Inhibitor ◽

Umbrella Sampling ◽

Coarse Grained ◽

Nucleotide Polymorphisms

Multidrug resistance protein-4 (MRP4) belongs to the ABC transporter superfamily and promotes the transport of xenobiotics including drugs. A non-synonymous single nucleotide polymorphisms (nsSNPs) in the ABCC4 gene can promote changes in the structure and function of MRP4. In this work, the interaction of certain endogen substrates, drug substrates, and inhibitors with wild type-MRP4 (WT-MRP4) and its variants G187W and Y556C were studied to determine differences in the intermolecular interactions and affinity related to SNPs using protein threading modeling, molecular docking, all-atom, coarse grained, and umbrella sampling molecular dynamics simulations (AA-MDS and CG-MDS, respectively). The results showed that the three MRP4 structures had significantly different conformations at given sites, leading to differences in the docking scores (DS) and binding sites of three different groups of molecules. Folic acid (FA) had the highest variation in DS on G187W concerning WT-MRP4. WT-MRP4, G187W, Y556C, and FA had different conformations through 25 ns AA-MD. Umbrella sampling simulations indicated that the Y556C-FA complex was the most stable one with or without ATP. In Y556C, the cyclic adenosine monophosphate (cAMP) and ceefourin-1 binding sites are located out of the entrance of the inner cavity, which suggests that both cAMP and ceefourin-1 may not be transported. The binding site for cAMP and ceefourin-1 is quite similar and the affinity (binding energy) of ceefourin-1 to WT-MRP4, G187W, and Y556C is greater than the affinity of cAMP, which may suggest that ceefourin-1 works as a competitive inhibitor. In conclusion, the nsSNPs G187W and Y556C lead to changes in protein conformation, which modifies the ligand binding site, DS, and binding energy.

Download Full-text