Virtual Screening and Discovery of Novel Aurora Kinase Inhibitors

Abstract

Cancer remains one of the major contributors to human mortality and a hazard to human growth. The search for a new treatment continues unabated. Aurora kinases play an important role in cell cycle, and thus a potential target for the treatment of cancer. In the present work, we aim to discover potential leads against aurora kinase using various rational methods of drug discovery. The available crystal complexes of AKs were analyzed for their interactions and quantified with glide-extra precision (XP) docking. About 20 crystal pdb were selected from the protein databank based on the resolution factor, R-factor and R-value. And after docking with the native ligands, the RMSD value was calculated, wherein the protein with the least RMSD was found to be 3UOK which was further used for our screening of small molecules from the in-house database by molecular docking. Fragments which were found to possess the best interactions were considered for the synthesis with characterization, and biological activity was carried out against breast cancer and colorectal cancer cell lines to assess the inhibitory capability of synthesized compounds. Molecule with the molecular id IS2 i.e. (3E)-3-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2H chromene-2,4(3H)-dione was found to possess inhibitory activity with an IC50 of 1.324 nM and 5.785 µM for breast cell line and colorectal cell line studies, respectively.

Diaryl ether derivative inhibits GPX4 expression levels to induce ferroptosis in thyroid cancer cells

“…MD protocol followed minimization, heating, equilibration, and production run. Minimization, heating, equilibration, and manufacturing run were all part of the MD process (Raghu et al, 2014). The OPLS4 force field was used to minimize the protein‐ligand complexes, and topology and atomic coordinates were obtained automatically (Shivakumar et al, 2010).…”

Interaction Between 2‐Methylimidazole and 1‐Butanol/1‐Octanol: Thermophysical and Computational Studies

“…The protocol included the process of heating, equilibration and minimization. [17] Topology, atomic coordinates and minimisation were acquired automatically using OPLS4 force field. [18] The binary mixtures were simulated for 100 ns at different temperatures.…”

“…In this case Desmond programme has been used to perform the simulations of 2‐methylimidazole‐1‐butanol and 2‐methylimidazole‐1‐Octanol to exhibit a picture of interaction between the constituents in the binary mixture. The protocol included the process of heating, equilibration and minimization [17] . Topology, atomic coordinates and minimisation were acquired automatically using OPLS4 force field [18] .…”

Identification of Novel Aurora Kinase A (AURKA) Inhibitors via Hierarchical Ligand-Based Virtual Screening

“…Virtual screening (VS) is a chemical library searching approach that aims to find novel compounds with a required biological activity as alternatives to existing ligands . VS has already been widely used to identify novel inhibitors for biological targets, including AURKA. , VS can be divided into two broad categories, namely structure-based virtual screening (SBVS) and ligand-based virtual screening (LBVS) . SBVS utilizes the structural information on the biological target and typically is based on molecular docking, which is computationally expensive when applied to a large database .…”