"Exploration of Novel Anticancerous Agents Targeting Human Aurora Kinase C".

in Journal of cellular biochemistry by Deepali Gupta, Prakash Kumar Shukla, Subarnarekha Chowdhury, Supriya Kumari, Punit Kaur, Mukesh Kumar

TLDR

  • The study uses computational methods to identify potent inhibitors of Aurora Kinase C (AKC) as a potential target for cancer therapy.
  • The study identifies three top candidates that interact with AKC's ATP binding pocket and have potential as potent inhibitors.
  • Additional studies are needed to confirm the therapeutic potential of the identified candidates.

Abstract

Aurora kinases (AKs), a family of serine/threonine kinases, play a vital role in chromosome segregation during the cell cycle (Mountzios et al., 2008). This family includes Aurora Kinase A (AKA), Aurora Kinase B (AKB), and Aurora Kinase C (AKC). AKA and AKB are active during mitosis, while AKC is involved mostly in germ cell as well as somatic cells. Elevated levels of AKC have been found in several cancer cell lines including breast, cervical, thyroid, colorectal, and liver cancers, making it a significant target for cancer therapy (Tang et al., 2017). In cancers such as glioblastoma and prostate cancer, for example, AKC up regulation has been associated with increased tumor aggressiveness, highlighting its potential role in tumor progression and poor prognosis. Our study employs computational methods, including molecular docking and structure-based virtual screening, to explore a data set of 2 65 241 compounds from the National Cancer Institute (NCI) database, focusing on AKC as a potential target for drug discovery. Through docking studies, several promising compounds that interact with the enzyme's ATP binding pocket, particularly with residues Phe54, Lys72, Ala123, Glu121 and Glu127 of AKC, were identified. The stability of these interactions was assessed through 200-ns molecular dynamics (MD) simulations, revealing that the majority of compounds exhibited stable interactions, while a few displayed fluctuations in their trajectories. Most compounds adhered to favorable pharmacokinetic properties. Comprehensive MD simulations and free energy calculations identified three top candidates (90 729, 37 623, and 134 546) with strong potential as potent inhibitors of AKC. Additional in vitro and in vivo studies are required to confirm the therapeutic potential of these candidates.

Overview

  • The study focuses on exploring Aurora Kinase C (AKC) as a potential target for cancer therapy and identifying potent inhibitors.
  • The study employs computational methods, including molecular docking and structure-based virtual screening, to identify promising compounds that interact with AKC's ATP binding pocket.
  • The primary objective is to identify potent inhibitors of AKC to develop novel therapies for various types of cancers.

Comparative Analysis & Findings

  • The study identified several promising compounds through docking studies that interact with AKC's ATP binding pocket, particularly with residues Phe54, Lys72, Ala123, Glu121, and Glu127.
  • Molecular dynamics (MD) simulations revealed that the majority of compounds exhibited stable interactions, while a few displayed fluctuations in their trajectories.
  • Comprehensive MD simulations and free energy calculations identified three top candidates (90 729, 37 623, and 134 546) with strong potential as potent inhibitors of AKC.

Implications and Future Directions

  • The study identifies AKC as a significant target for cancer therapy, and the identified candidates have potential as potent inhibitors.
  • Additional in vitro and in vivo studies are required to confirm the therapeutic potential of the identified candidates.
  • Future research can build on the results to explore novel approaches for cancer therapy and address the limitations of the current study.
Read Full Article