Identification of Potent Inhibitors against Aurora Kinase A Using Molecular Docking and Molecular Dynamics Simulation Studies

Abstract

Aurora kinase A (AURKA) is a normal cell proliferation-inducing enzyme encoded by AURKA gene, with over-expression observed in different types of malignancies. Hence, the goal is to find potential inhibitors against AURKA. In this study, molecular docking, Standard Precision and Extra Precision methods were employed. After the docking study, the ligands showed an extremely low binding score which suggested very high binding affinity of the ligands. Furthermore, Quantum polarized ligand docking (QPLD) was performed to predict the binding status of the molecules. Based on the binding affinity, the top four compounds were chosen for further analysis. The docked complexes were further analyzed in explicit water conditions using 100 ns molecular dynamics simulations and binding free energy calculation. Then, density functional theory (DFT) calculation was used to calculate the molecular properties of the molecules. Finally, systems biology experiments validated the molecular docking and molecular dynamics simulation studies and indicated that quercetin, kaempferol, luteolin and rutin could inhibit the AURKA. The results show that, these four molecules have high binding affinity to the AURKA and significant interactions (LEU139, GLU211and ALA213) were also identified with the hinge region of Aurora kinase A. Thus, LEU139, GLU211, and ALA213 were identified as the crucial protein mechanisms.

In Silico and In Vitro Screening of Natural Compounds as Broad-Spectrum β-Lactamase Inhibitors against Acinetobacter baumannii New Delhi Metallo-β-lactamase-1 (NDM-1)

“…This is derived from a single-point calculation for the QM region using density functional theory using the 6-31G∗/LACVP∗ basis set, B3LYP density functional, and “Ultrafine” SCF accuracy level (iacc = 1 and iacscf = 2) [ 18 ]. Briefly, three steps were included in the protocol: first, generating the best pose for ligand docking using standard precision (SP) scoring mode followed by XP refinement; second, initial partial charges on ligand atoms were removed, and QM-ESP charges were calculated from the electrostatic potential energy surface of the ligand, generated from a single-point calculation using B3LYP/6-31G∗ level within the protein environment and density function for the QM region; and third, the ligands were redocked in the most energetically favourable pose using Glide standard docking for QPLD refinement, and then, the level of quantum–mechanical treatment was set at Fast mode [ 19 ].…”

“…The colour-coded surface values showed the positive electrostatic potentials and total molecular size. The most positive electrostatic potential regions are indicated by the darkest blue colour, whereas the most negative electrostatic potential regions are indicated by the deepest red colour [ 19 , 21 ].…”

Identification of polypharmacological anticancerous molecules against Aurora kinase family of proteins

“…These interactions are critical and have been reported to be retained for other small molecule inhibitors, quercetin, kaempferol, luteolin, and rutin. 54 The residues, Phe88, Ala157, and Glu161 in AURK-B were observed to form stable hydrogen bonding interactions with ligand molecules (2818, 5326, and 7447) for more than 30% of simulation time (Figures 6A,B, 7A,B, and S4A,B respectively). The timeline plot indicates the stability of these interactions during the entirety of simulation time (Figures 6C, 7C, S4C, respectively).…”

“…The timeline plot of 5326 and 7447 indicated the retention of interactions mediated by Leu139 and Ala213 throughout the simulation time. These interactions are critical and have been reported to be retained for other small molecule inhibitors, quercetin, kaempferol, luteolin, and rutin 54 …”

<em>Plasmodium falciparum</em> Dihydroorotate Dehydrogenase, Fragment-based Drug Design, 2D-QSAR, DFT Calculation, Lead Optimization, Induced Fit Docking

“…The MESP map of the compounds illustrated in Figure 9. These sites provide information on the atoms of the compounds that can form non-covalent interactions [45].The values of MEP at the surface of the compounds are represented by different colors, red color signifies the regions of the most electro negative electrostatic potential, blue color shows the regions of the most electro positive electrostatic potential, and the grey color represent the region with zero potential. Therefore, the electrostatic potential increases in the order red <grey < blue.…”