New phosphoramides containing imidazolidine moiety as anticancer agents: an experimental and computational study

2022 ◽  
pp. 105617
Author(s):  
Khodayar Gholivand ◽  
Mohammad Faraghi ◽  
Nasrin Fallah ◽  
Mohammad Satari ◽  
Mahsa Pooyan
Keyword(s):  
Anticancer Agents ◽  
Computational Study

scholarly journals Combinatorial Library Designing and Virtual Screening of Cryptolepine Derivatives against Topoisomerase II by Molecular Docking

2020 ◽  
Author(s):  
Maria ◽  
Zahid Khan
Keyword(s):  
Molecular Docking ◽  
Cell Division ◽  
Binding Energy ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Combinatorial Library ◽  
Topoisomerase Ii ◽  
Computational Study ◽  
Binding Energies ◽  
Potential Inhibitors

AbstractComputational approaches have emerging role for designing potential inhibitors against topoisomerase 2 for treatment of cancer. TOP2A plays a key role in DNA replication before cell division and thus facilitates the growth of cells. This function of TOP2A can be suppressed by targeting with potential inhibitors in cancer cells to stop the uncontrolled cell division. Among potential inhibitors cryptolepine is more selective and has the ability to intercalate into DNA, effectively block TOP2A and cease cell division in cancer cells. However, cryptolepine is non-specific and have low affinity, therefore, a combinatorial library was designed and virtually screened for identification of its derivatives with greater TOP2A binding affinities.A combinatorial library of 31114 derivatives of cryptolepine was formed and the library was virtually screened by molecular docking to predict the molecular interactions between cryptolepine derivatives and TOP2A taking cryptolepine as standard. The overall screening and docking approach explored all the binding poses of cryptolepine for TOP2A to calculate binding energy. The compounds are given database number 8618, 907, 147, 16755, and 8186 scored lowest binding energies of −9.88kcal/mol, −9.76kcal/mol, −9.75kcal/mol, −9.73kcal/mol, and −9.72kcal/mol respectively and highest binding affinity while cryptolepine binding energy is −6.09kcal/mol. The good binding interactions of the derivatives showed that they can be used as potent TOP2A inhibitors and act as more effective anticancer agents than cryptolepine itself. The interactions of derivatives with different amino acid residues were also observed. A comprehensive understanding of the interactions of proposed derivatives with TOP2A helped for searching more novel and potent drug-like molecules for anticancer therapy. This Computational study suggests useful references to understand inhibition mechanisms that will help in the modification of TOP2A inhibitors.

Combinatorial library design and virtual screening of cryptolepine derivatives against topoisomerase IIA by molecular docking and DFT studies

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Maria ◽  
Zahid Khan ◽  
Aleksey E. Kuznetsov
Keyword(s):  
Molecular Docking ◽  
Cell Division ◽  
Binding Energy ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Combinatorial Library ◽  
Computational Study ◽  
Binding Energies ◽  
Binding Affinities ◽  
Potential Inhibitors

Abstract Various computational approaches have received ever-growing role in the design of potential inhibitors of the topoisomerase 2 (TOP2A) for cancer treatment. TOP2A plays a key role in the deoxyribonucleic acid (DNA) replication before cell division and thus facilitates the growth of cells. This TOP2A function can be suppressed by targeting it with potential inhibitors in cancer cells to terminate the uncontrolled cell division. Among potential inhibitors, cryptolepine has higher selectivity along with the ability to intercalate into DNA, effectively blocking TOP2A and ceasing cell division in cancer cells. However, this compound has drawbacks of being nonspecific and possessing relatively low affinity. Therefore, a combinatorial library of 31,114 cryptolepine derivatives was designed and virtually screened by molecular docking to predict the molecular interactions between the cryptolepine derivatives and TOP2A using cryptolepine as a standard. All the binding poses of cryptolepine derivatives for TOP2A were investigated to calculate binding energy. The compounds with the database numbers 8618, 907, 147, 16755, and 8186 scored the highest binding energies, −9.88, −9.76, −9.75, −9.73, and −9.72 kcal/mol, respectively, and the highest binding affinities while the cryptolepine binding energy is −6.09 kcal/mol. The strong binding interactions of these derivatives show that they can be used as potent TOP2A inhibitors and act as more effective anticancer agents than cryptolepine itself. The interactions of these derivatives with different amino acid residues were also observed and analyzed. A comprehensive understanding of the interactions of the proposed derivatives with TOP2A helped for searching more novel and potent drug-like molecules for anticancer therapy. This computational study suggests useful references to understand inhibition mechanisms that will help in the further modifications of TOP2A inhibitors. Moreover, the DFT study of the derivatives with the highest binding energies was performed, helping to further understand the binding affinities of these compounds.

Discovery of structural prospects of imidazo[1,5-a]pyrazine derivatives as BTK inhibitors against cancer: A computational study

2021 ◽  
Vol 18 ◽  
Author(s):  
Amena Ali ◽  
Abuzer Ali ◽  
Mohamed Jawed Ahsan
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Anticancer Agents ◽  
Oral Absorption ◽  
Computational Study ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Pharmacokinetic Parameters ◽  
Pharmacophore Hypothesis ◽  
Btk Inhibitors

Background: Bruton’s tyrosine kinase (BTK) plays an important role in cell development and proliferation. BTK inhibitors are encouraging novel agents against B-cell malignancies and autoimmune diseases. Although BTK inhibitors have been approved by the FDA, but to lower off-target effects and to reduce emerging resistances, it is necessary to develop novel BTK inhibitors with better outcomes and minimum side effects. Objective: The present study includes pharmacophore hypothesis, 3D QSAR, virtual screening, docking, ADME analysis and screening of potential imidazo[1,5-a]pyrazine derivatives as BTK inhibitors. Methods: Generation of pharmacophore hypothesis, virtual screening, 3D QSAR, molecular docking and ADME analysis. Methods: Generation of pharmacophore hypothesis, virtual screening, 3D QSAR, molecular docking and ADME analysis. Results: Pharmacophore study generated 20 pharmacophore hypotheses as BTK inhibitor. The five-point hypothesis DPRRR_1 were selected, consist one hydrogen bond donor, one positive ionic, and three ring aromatic features. 3D QSAR study of the compounds provided the best model with high Q2 (0.8683), R2 (0.983) and R2CV (0.5338) values. The developed pharmacophore model was further taken for screening of ZINC database ligands for evaluation of docking interaction and physiochemical properties. Potent compounds of the series 15, 27, 8n and 38 showed good docking scores -8.567, -7.465, -6.922, -6.137, respectively. Conclusion: All the pharmacokinetic parameters analysed, including human oral absorption of active compounds of the series were found to be within the permissible range. The present geometry and features included in pharmacophore hypothesis can be used for the development of novel BTK inhibitors as anticancer agents.

An ab initio study of model triazene-based anticancer agents

2010 ◽  
Vol 88 (8) ◽  
pp. 709-715 ◽  
Author(s):  
Katherine G. Doucet ◽  
Julie F. Glister ◽  
Cory C. Pye
Keyword(s):  
Ab Initio ◽  
Gas Phase ◽  
Anticancer Agents ◽  
Computational Study ◽  
Transition States ◽  
Ab Initio Study

A computational study of a series of model triazene-based anticancer agents based on methyl- and amidyl-substituted 5-(1-triazenyl)imidazoles has been carried out, including the drugs Dacarbazine, Temozolomide, and Mitozolomide. A number of different conformers are analyzed. The transition states for the gas-phase and water-mediated triazene tautomerization reaction are found and the barriers are determined.

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