title: Discovery of Camptothecin Based Topoisomerase I Inhibitors: Identification Using an Atom Based 3D-QSAR, Pharmacophore Modeling, Virtual Screening and Molecular Docking Approach.
abstract: BACKGROUND
  Camptothecin is a quinoline alkaloid, isolated from the Chinese tree Camptotheca acuminate which exhibits its cytotoxic activity by the inhibition of nuclear enzyme Topoisomerase I (topo I). Camptothecin and its analogues forms a covalent bond with DNA which can arrest the tumor growth by slowing the religation step of the enzyme and stabilize the covalent adduct between topo I and DNA. Besides its strong anticancer potential, the limited solubility as well as instability of the hydroxylactone ring (Ring E) limits the clinical application of Camptothecin. This study was undertaken to identify novel compounds having anticancer activity with mechanism of action similar to that of Camptothecin using scaffold perception technique.
  
  
  METHODS
  We developed a common pharmacophore hypothesis using 32 camptothecin analogues, which was used for preliminary screening of large databases (ZINC "drug-like" database) to make sure, to include only compounds containing the key structural features needed to be Topoisomerase I inhibitors. In terms of a structure based approach, we systematically investigated various types of docking protocols to identify the most active compounds from the identified hit molecules. A post docking energy calculation was also carried out by MM/GBSA method.
  
  
  RESULTS
  From the selected series of camptothecin analogs, a 3D-QSAR pharmacophore model was developed. The model consists of one acceptor site, one donor site, one hydrophobic site and two aromatic functions (ADHRR). Then, the pharmacophore model was employed as 3D search query to screen compounds from ZINC database which followed by molecular docking study and MM/GBSA calculation identified 2 lead molecules which, however, were not biologically validated. In silico studies reveals that the identified lead molecules have a better binding affinity than the co crystallized ligand.
  
  
  CONCLUSIONS
  The identified molecules were able to bind to the active site of Topo-I enzyme similar to that of Camptothecin and the ADME properties were within the acceptable range defined for human use. The new molecules identified by virtual screening as such or on further optimization can be used as potential leads in designing Topoisomerase I inhibitors.
authors: Department of Pharmaceutical Chemistry, Al Shifa College of Pharmacy, Perintalmanna, Kerala 679325, India. sanaldev@gmail.com.
authors: Sanal
authors: S
authors: Dev
authors: Sunil R
authors: SR
authors: Dhaneshwar
authors: Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad 678557, Kerala, India. bijovilaventgu@gmail.com.
authors: Bijo
authors: B
authors: Mathew
mesh_terms: D002166:Camptothecin / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D021281:Quantitative Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000737:chemistry*
chemical_list: D059004:Topoisomerase I Inhibitors; D002166:Camptothecin