Title:Discovery of Camptothecin Based Topoisomerase I Inhibitors: Identification Using an Atom Based 3D-QSAR, Pharmacophore Modeling, Virtual Screening and Molecular Docking Approach
Volume: 19
Issue: 9
Author(s): Sanal Dev, Sunil R. Dhaneshwar and Bijo Mathew
Affiliation:
Keywords:
Camptothecin, virtual screening, topoisomerase, pharmacophore modeling, molecular docking.
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.
Materials and 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.
Conclusion: 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.
