title: Abrogation of AuroraA-TPX2 by novel natural inhibitors: molecular dynamics-based mechanistic analysis.
abstract: BACKGROUND
  Cancer is characterized by uncontrolled cell growth and genetic instabilities. The human Aurora-A kinase protein plays a crucial role in spindle assembly during mitosis and is activated by another candidate oncogene, targeting protein for Xklp2 (TPX2). It has been proposed that dissociation of Aurora A-TPX2 complex leads to disruption of mitotic spindle apparatus, thereby preventing cell division and further tumor growth.
  
  
  METHODS
  A large natural compound library was docked against the active site of Aurora A-TPX2 complex. The protein-ligand complexes were subjected to molecular dynamics simulation to ascertain their binding stability. The drug properties of the compounds were analyzed to observe their drug-like properties.
  
  
  RESULTS
  The virtual screening of natural compound library yielded two high scoring compounds, the first compound CTOM [ZINC ID: 38143674] (Glide score: -9.49) was stable for 17 ns while the second TTOM (Glide score: -9.07) was stable for 15 ns. While CTOM interacted with His280, Thr288 of Aurora A and Tyr34, Lys38 of TPX2, TTOM interacted with Arg285 and Arg286 in addition to the residues involved with CTOM.
  
  
  CONCLUSIONS
  We report two natural compounds as potential drugs leads for the disruption of this complex. These ligands show a preferable docking score and have many drugs like properties within in the range of 95% of known drugs. The study provides evidence that CTOM and TTOM can efficiently inhibit the TPX2-mediated activation of Aurora A. Thus, it paves way for an elaborate investigation and establishes the importance of computational approaches as time- and cost-effective techniques.
authors.affiliation: a Department of Biotechnology , Delhi Technological University , New Delhi , India and.
authors.forename: Ankita
authors.initials: A
authors.lastname: Gupta
authors.affiliation: b School of Biotechnology, Jawaharlal Nehru University , New Delhi , India.
authors.forename: Ritu
authors.initials: R
authors.lastname: Jain
authors.affiliation: b School of Biotechnology, Jawaharlal Nehru University , New Delhi , India.
authors.forename: Divya
authors.initials: D
authors.lastname: Wahi
authors.affiliation: b School of Biotechnology, Jawaharlal Nehru University , New Delhi , India.
authors.forename: Sukriti
authors.initials: S
authors.lastname: Goyal
authors.affiliation: b School of Biotechnology, Jawaharlal Nehru University , New Delhi , India.
authors.forename: Salma
authors.initials: S
authors.lastname: Jamal
authors.affiliation: b School of Biotechnology, Jawaharlal Nehru University , New Delhi , India.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
mesh_terms: D064096:Aurora Kinase A / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D001688:Biological Products / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D001688:Biological Products; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D054852:Small Molecule Libraries; C122167:TPX2 protein, human; C576917:AURKA protein, human; D064096:Aurora Kinase A
keywords: Aurora A; TPX2; cancer; inhibitors; molecular dynamics; natural; simulations