title: Virtual screening studies reveal linarin as a potential natural inhibitor targeting CDK4 in retinoblastoma.
abstract: OBJECTIVE
  To find out whether linarin can be used as a potential natural inhibitor to target CDK4 in retinoblastoma using virtual screening studies.
  
  
  METHODS
  In this study, molecular modeling and protein structure optimization was performed for crystal structure of CDK4 (PDB id: 3G33), and was subjected to Molecular Dynamics (MD) simulation for 10 nanoseconds, as a preparatory process for docking. Furthermore, the stable conformation obtained in the MD simulation was utilized for virtual screening against the library of natural compounds in Indian Plant Anticancer Compounds Database (InPACdb) using AutoDock Vina. Finally, best docked ligands were revalidated individually through semi-flexible docking by AutoDock 4.0.
  
  
  RESULTS
  The CDK4 structure was stereochemically optimized to fix clashes and bad angles, which placed 96.4% residues in the core region of Ramachandran plot. The final structure of CDK4 that emerged after MD simulation was proven to be highly stable as per different validation tools. Virtual screening and docking was carried out for CDK4 against optimized ligands from InPACdb through AutoDock Vina. This inferred Linarin (Inpacdb AC.NO. acd0073) as a potential therapeutic agent with binding energy of -8.9 kJ/mol. Furthermore, it was also found to be valid as per AutoDock 4.0 semi-flexible docking procedure, with the binding energy of -8.18 kJ/mol and Ki value of 1.01 μM.
  
  
  CONCLUSIONS
  The docking results indicate linarin, a flavonoid plant compound, as a potential inhibitor of CDK4 compared to some of the currently practiced anticancer drugs for retinoblastoma. This finding can be extended to experimental validation to assess the in vivo efficacy of the identified compound.
authors.affiliation: Center for Bioinformatics, Vision Research Foundation, Sankara Nethralaya, College Road, Chennai, Departement of Bioinformatics, Sastra University, Tirumalaisamudram, Thanjavur, Tamilnadu, India.
authors.forename: Muthukumaran
authors.initials: M
authors.lastname: Sivashanmugam
authors.forename: Chandana
authors.initials: C
authors.lastname: Raghunath
authors.forename: Umashankar
authors.initials: U
authors.lastname: Vetrivel
keywords: Cyclin-dependent kinase 4; InPACdb; molecular docking; molecular dynamics; retinoblastoma; virtual screening