scholarly journals CHEMICAL STRUCTURE OPTIMIZATION OF LUPEOL AS ER-Α AND HER2 INHIBITOR

2018 ◽  
Vol 11 (6) ◽  
pp. 298 ◽  
Author(s):  
Mohammad Rizki Fadhil Pratama ◽  
Sutomo S
Keyword(s):  
Breast Cancer ◽  
Free Energy ◽  
Chemical Structure ◽  
Structure Optimization ◽  
Basis Set ◽  
Amino Acid Residues ◽  
Her2 Positive ◽  
Hartree Fock ◽  
Anticancer Properties ◽  
Free Energy Of Binding

Objectives: Lupeol, a triterpenoid isolated from Kasturi (Mangifera casturi) fruit has been known for having several pharmacological activities, including anticancer properties. Lupeol showed antiproliferative activity toward many cancer cells line including breast cancer. Lupeol showed promising potency as both ER-α and HER2 inhibitors, although still lower than known ER-α and HER2 Inhibitors. Chemical structure optimization of lupeol was predicted could increase the affinity of lupeol derivatives against ER-α and HER2. This study aims to determine lupeol derivative with the highest affinity against ER-α and HER2.Methods: All ligands were sketched and optimized using Gaussian 03W with Hartree–Fock method basis set 3-21G. Molecular docking was performed using Autodock 4.2.6 on several modified chemical structure of lupeol against active site of ER-α and HER2. The main parameter used was the free energy of binding and inhibition constants as affinity marker.Results: The docking results show that lupeol derivative with an amine group (Lupeol-2) and ethyl group (Lupeol-4) at position C3 provide the highest affinity with the free energy of binding and dissociation constant −12.24 kcal/mol and 1.07 nM for ER-α also −9.63 kcal/mol and 86.94 nM for HER2, respectively. Interestingly, although lupeol derivatives showed higher affinity toward ER-α, their amino acid residues were closer to the interaction on HER2.Conclusion: These results predict that lupeol have greater potential to be developed as a HER2 inhibitor. Further, derivate lupeol-4 should be potential to be developed as HER2-positive breast cancer therapy.

scholarly journals NUMBER OF RUNS VARIATIONS ON AUTODOCK 4 DO NOT HAVE A SIGNIFICANT EFFECT ON RMSD FROM DOCKING RESULTS

2021 ◽  
Vol 8 (6) ◽  
pp. 476-480
Author(s):  
M.R.F. Pratama ◽  
S. Siswandono
Keyword(s):  
Free Energy ◽  
Estrogen Receptor ◽  
Amino Acid ◽  
Hydrogen Bonds ◽  
Linear Equation ◽  
Significant Contribution ◽  
Amino Acid Residues ◽  
Maximum Difference ◽  
Binding Inhibition ◽  
Free Energy Of Binding

The aim. The number of runs in the docking process with AutoDock 4 is known to play an important role in the validity of the results obtained. The greater the number of runs it is often associated with the more valid docking results. However, it is not known exactly how the most ideal runs in the docking process with AutoDock 4. This study aims to determine the effect of the number of runs docking processes with AutoDock 4 on the validity of the docking results.Materials and methods. The method used is the redocking process with AutoDock 4.2.6. The receptor used is an estrogen receptor with ligand reference estradiol (PDB ID 1GWR). Variations were made on the number of runs from 10 to 100 in multiples of 10. The parameters observed were RMSD, free energy of binding, inhibition constants, amino acid residues, and the number of hydrogen bonds.Results. All experiments produce identical bond free energy, where the maximum difference in inhibition constant is only 0.06 nM. The lowest RMSD is indicated by the number of runs of 60, with a RMSD value of 0.942. There is no linear relationship between the number of runs and RMSD, with R in the linear equation of 0.4607.Conclusion. Overall, the number of runs does not show a significant contribution to the validity of the results of docking with AutoDock 4. However, these results have only been proven with the receptors used.

scholarly journals Identification of a putative anti-rheumatoid arthritis molecule by virtual screening

2020 ◽  
Vol 19 (6) ◽  
pp. 1255-1261
Author(s):  
Shazi Shakil ◽  
Adel M Abuzenadah ◽  
Suzan M. Attar ◽  
Omar Fathaldin ◽  
Rajaa Al-Raddadi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Free Energy ◽  
Virtual Screening ◽  
Thymidylate Synthase ◽  
Molecular Descriptors ◽  
Amino Acid Residues ◽  
Methotrexate Interaction ◽  
Inhibitor Design ◽  
Interaction Site ◽  
Free Energy Of Binding

Purpose: To propose an improved chemical skeleton whose scaffolds could be used for the design of future thymidylate synthase (TS)-inhibitors against rheumatoid arthritis. Methods: The drug discovery platform, ‘MCULE’, was employed for inhibitor-screening. The ‘methotrexate-interaction site’ in the crystal (PDB ID 5X66) was used as a target. One ‘RO5 violation’ was permitted. A maximum of ‘10 rotatable bonds’ and ‘100 diverse molecules’ were also allowed in the protocol. The ‘threshold similarity cut off’ was 0.7. The input values describing the remaining parameters were kept as ‘default’. The ‘Open Babel Linear Fingerprint’ was used for the analyses of molecular descriptors, followed by ADME-check. Results: 4-(4-Methyl-1-piperazinyl)-2-phenyl[1]benzofuro[3,2-d]pyrimidine corresponding to the MCULE ID-7590816301-0-93 exhibited the overall best binding with TS. The free energy of binding was -8.6 kcal/mol. A total of 17 amino acid residues were significant for the binding interactions. Importantly, 9 residues were common to methotrexate binding. It satisfied pertinent ADME conditions. Conclusion: 4-(4-Methyl-1-piperazinyl)-2-phenyl[1]benzofuro[3,2-d]pyrimidinemay emerge as a potent seed molecule for TS-inhibitor design in the context of rheumatoid arthritis. It has satisfied pertinent ADME features. However, there is need for further wet laboratory validation. Keywords: Anti-rheumatoid arthritis, Inhibitor design, Methotrexate, Seed molecule, Thymidylate synthase, Virtual screening

3D WAVELET TREATMENT OF SOLVATED BIPOLARON AND POLARON

2005 ◽  
Vol 04 (03) ◽  
pp. 751-767 ◽  
Author(s):  
G. N. CHUEV ◽  
M. V. FEDOROV ◽  
H. J. LUO ◽  
D. KOLB ◽  
E. G. TIMOSHENKO
Keyword(s):  
Free Energy ◽  
Three Dimensional ◽  
Energy Functional ◽  
Wave Functions ◽  
Basis Set ◽  
Electron Wave ◽  
Solvated Electron ◽  
Hartree Fock ◽  
Free Energy Functional ◽  
Excess Electrons

Three-dimensional discrete tensor wavelets are applied to calculate wave functions of excess electrons solvated in polar liquids. Starting from the Hartree–Fock approximation for the electron wave functions and from the linear response to the solute charge for the solvent, we have derived the approximate free energy functional for the excess electrons. The orthogonal Coifman basis set is used to minimize the free energy functional and to approximate the electron wave functions. The scheme is applied to the calculation of the properties of the solvated electron and the singlet bipolaron formation. The obtained results indicate that the proposed algorithm is fast and rather efficient for calculating the electronic structure of the solvated molecular solutes.

Co-expression of ER-beta and HER2 associated with poorer prognosis in primary breast cancer

2009 ◽  
Vol 32 (3) ◽  
pp. 250 ◽  
Author(s):  
Wen-sheng Qui ◽  
Lu Yue ◽  
Ai-ping Ding ◽  
Jian Sun ◽  
Yang Yao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Differentiation ◽  
Primary Breast Cancer ◽  
Tumour Size ◽  
Univariate Analysis ◽  
Growth Factor Receptor ◽  
Disease Free Survival ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Er Alpha

Purpose: To assess the prognostic value of co-expression of estrogen receptor (ER)-beta and human epidermal growth factor receptor 2 (HER2) in primary breast cancer patients in China. Methods: Tumour specimens from 308 patients undergoing surgery for primary breast cancer were evaluated. Expression of ER-beta and HER-2 was investigated by the immunohistochemistry. Results: 123 patients (40%) were ER-beta positive and 58 (18.5 %) were HER2 positive. Among the 58 HER2 positive patients, 44 were ER-beta positive and 14 were ER-beta negative. ER-beta positive was associated with HER2 positive (75.9%, P=0.018) as well as ER-alpha positive (79.7%, P=0.023), poor cell differentiation (77.2% grade 2 or 3, P=0.010) and menopause age < 45 yr (55.3%, P=0.031). HER2 positive was associated with poor cell differentiation (93.1%, P=0.001), ?3cm tumour size (67.2%, P=0.011). Conclusion: Both ER-beta positive and HER2 positive status was associated with poorer overall survival (OS) by univariate analysis. In both HER2 positive and HER2 negative subgroups, ER-beta positive was associated with poorer distant disease free survival (DDFS) but not OS, which implied that ER-beta might relate to metastasis in breast cancer.

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