What is it about?

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. 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). 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 was performed 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. Out of 56 derivatives, 11 have passed all the rules of drug candidature, to serve as best AKs inhibitor, in a theoretical manner.

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Why is it important?

In summary, fifty six derivative analogs of RA have been theoretically investigated as AKs inhibitors. This systematic study has been carried out in three different parts: (1) electronic and quantum mechanical study of compounds using DFT at UB3LYP level of 6-311++G(d,p) basis set, (2) molecular docking study of each molecule in the active site of AKs, (3) drug-likeness and toxicity prediction and comparing its results with standard drug RA. Comparative docking study of molecules shows that RA50, RA4, RA5, RA13, RA23, RA47 have considerable binding energy, out of which RA50 has the highest. But all of these fail to act like drug because of usual deviation from quantum mechanical parameters (high band gap, low softness) and disobey Lipinski rule of five or from both concerned. Considering the quantum mechanical, electronic properties obtained from DFT, molecular docking studies and also drug-likeness, toxicity parameters show that the analogs RA9, RA10, RA11, RA12, RA17, RA32, RA42, RA46, RA48, RA55 and RA56 have been predicted to be more chemically reactive, good drug-like behavior, contain low toxicity with higher absolute value of ligand binding energies (-8.38─ -9.77Kcal/mol). In conclusion, these eleven analogs could be considered as lead molecules to enhance their therapeutic index by enhancing interactions with the target protein.

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This page is a summary of: Screening of Drug Efficacy of Rosmarinic Acid Derivatives as Aurora Kinase Inhibitors by Computer-Aided Drug Design Method, Current Computer - Aided Drug Design, November 2021, Bentham Science Publishers,
DOI: 10.2174/1573409916666200703170045.
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