Screening of drug efficacy of Rosmarinic Acid derivatives as Aurora kinase inhibitors by computer aided drug design method

Background: Aurora kinases (AKs) belong to serine/threonine kinase family, play a crucial role in regulating the cell cycle. Therefore, AKs are the hopeful target for anticancer therapies and these finding have appreciated researchers to rigorous hunting of small molecule aurora kinase inhibitors, not only for research articles but also use as therapeutic agent. Objective: The present study helps us to identify and screen best phytochemicals as potent inhibitors against AKs. These potent inhibitors are coming from various substitution of rosmarinic acid (RA). Methods: In this paper, we choose different tested derivative compounds for designing anticancer drugs by substituting various functional groups of standard drug RA. In silico studies were carried out, in an effort to appreciate better drug candidature of some of these derivative compounds. This study wasperformed on 56 derived compounds of standard RA. DFT study was done using UB3LYP/6-311G++G(d,p) basis set to study HOMO-LUMO energies, dipole moments, using Gaussian16 suite. Some of the derived parameters, like ionization potential, electron affinity, softness-hardness, chemical potential and electrophilicity index were noted. Docking study was performed with AKs inhibiting receptor using AutoDock 4.2. ADME prediction was done with preADMET web tool. Molecular descriptor properties were predicted with molinspiration and OSIRIS property explorer. Results: Out of 56 derivatives, 11 have passed all the rules of drug candidature, to serve as best AKs inhibitor, in a theoretical manner. Conclusions: This study should be supported a new proposal to explore future studies with these 11 compounds against cancer.

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Selection the Drug Efficacy of Oroidin Derivatives as Hsp90 Inhibitors by Computer Aided Drug Design Method

International Journal of Pharmaceutical Sciences and Drug Research ◽

10.25004/ijpsdr.2020.120607 ◽

2020 ◽

pp. 630-651

Author(s):

Subhajit Sarkar ◽

Rajesh Kumar Das

Keyword(s):

Chemical Potential ◽

Design Method ◽

Molecular Descriptor ◽

Dipole Moments ◽

Binding Energies ◽

Basis Set ◽

Toxicity Tests ◽

In Vitro Test ◽

In Silico Studies

Heat shock protein 90 (Hsp90) is a conserved molecular chaperone associated with regulation of hundreds of client proteins that are key drivers, regulators and promoters of numerous refractory diseases including cancer. Consequently, Hsp90 is a significant target for the development of harmless anticancer therapies. Marine organisms are the rich source of pharmacological important compounds, especially oroidin. Oroidin, a pyrrole-2-aminoimidazole alkaloid, isolated from the marine sponge Agelas oroides, binds ATP pocket of Hsp90 and suppresses the ATPase activity of the protein. Natural product oroidin was selected as potent inhibitor of Hsp90 and its drug candidature was accordingly improved by substituting various functional groups. Virtual screenings were done through in silico studies, carried out on thirty nine derivatives of oroidin. DFT study was performed with Gaussian16, UB3LYP/6-311G++ (d, p) basis set to investigate the quantum mechanical parameters such as HOMO-LUMO energies, dipole moments. Derived parameters like ionization potential, electron affinity, softness-hardness, chemical potential and electrophilicity index were also calculated. Using AutoDock 4.0 programme, we studied docking of the thirty-nine designed derivatives with macromolecule Hsp90 and recorded the binding energy values of the best conformation out of nine in each docked compound. ADME predictions, molecular descriptor properties, and theoretical toxicity tests were evaluated using preADMET, molinspiration, and OSIRIS property explorer web tools respectively. We found twenty eight derived compounds, each docked at the same region of Hsp90, possessing higher binding energies compare to the precursor oroidin. Seven of them qualified all the rules of drug candidature and could be safe in using as effective drugs for cancer treatment. This study suggests that these compounds could be synthesized for in vitro test and may leads to a novel anticancer therapeutics.

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Aurora Kinase Inhibitors in Head and Neck Cancer

Current Topics in Medicinal Chemistry ◽

10.2174/1568026618666180112163741 ◽

2018 ◽

Vol 18 (3) ◽

pp. 199-213

Author(s):

Guangying Qi ◽

Jing Liu ◽

Sisi Mi ◽

Takaaki Tsunematsu ◽

Shengjian Jin ◽

...

Keyword(s):

Head And Neck Cancer ◽

Cancer Therapy ◽

Kinase Inhibitors ◽

Biological Function ◽

Aurora Kinase ◽

Aurora Kinases ◽

Related Research ◽

Chemotherapy Drugs ◽

Aurora Kinase Inhibitors

Aurora kinases are a group of serine/threonine kinases responsible for the regulation of mitosis. In recent years, with the increase in Aurora kinase-related research, the important role of Aurora kinases in tumorigenesis has been gradually recognized. Aurora kinases have been regarded as a new target for cancer therapy, resulting in the development of Aurora kinase inhibitors. The study and application of these small-molecule inhibitors, especially in combination with chemotherapy drugs, represent a new direction in cancer treatment. This paper reviews studies on Aurora kinases from recent years, including studies of their biological function, their relationship with tumor progression, and their inhibitors.

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