Target fishing of glycopentalone using integrated inverse docking and reverse pharmacophore mapping approach

Abstract

ABSTRACT. Glycopentalone isolated from Glycosmis pentaphylla (family Rutaceae) has cytotoxic and apoptosis inducing effects in various human cancer cell lines; however, its mode of action is not 2 A.B. gurung et al. Genetics and Molecular Research 15 (3): gmr.15038544 known. Therefore, target fishing of glycopentalone using a combined approach of inverse docking and reverse pharmacophore mapping approach was used to identify potential targets of glycopentalone, and gain insight into its binding modes against the selected molecular targets, viz., CDK-2, CDK-6, Topoisomerase I, Bcl-2, VEGFR-2, Telomere:Gquadruplex and Topoisomerase II. These targets were chosen based on their key roles in the progression of cancer via regulation of cell cycle and DNA replication. Molecular docking analysis revealed that glycopentalone displayed binding energies ranging from -6.38 to -8.35 kcal/mol and inhibition constants ranging from 0.758 to 20.90 µM. Further, the binding affinities of glycopentalone to the targets were in the order: Telomere:G-quadruplex > VEGFR-2 > CDK-6 > CDK-2 > Topoisomerase II > Topoisomerase I > Bcl-2. Binding mode analysis revealed critical hydrogen bonds as well as hydrophobic interactions with the targets. The targets were validated by reverse pharmacophore mapping of glycopentalone against a set of 2241 known human target proteins which revealed CDK-2 and VEGFR-2 as the most favorable targets. The glycopentalone was well mapped to CDK-2 and VEGFR-2 which involve six pharmacophore features (two hydrophobic centers and four hydrogen bond acceptors) and nine pharmacophore features (five hydrophobic, two hydrogen bond acceptors and two hydrogen bond donors), respectively. The present computational approach may aid in rational identification of targets for small molecules against large set of candidate macromolecules before bioassays validation.

The Use of Methods of Computer-Aided Drug Discovery in the Development of Topoisomerase II Inhibitors: Applications and Future Directions

“…These include reverse docking, binding mode identification, and ligand–protein interaction studies. Using reverse docking, researchers pinpointed TopoII as a potential target of several molecules with antiproliferative potential. ,, By comparing docking scores derived from different TopoII drug pockets, binding modes and molecular mechanisms of action of several compounds were elucidated. ,,, …”

“…To our knowledge, all reverse docking studies with TopoII relied on the crystal structure of its ATPase domain (PDB 1ZXM), and therefore, only the catalytic mode of drug action was considered. Thus, the reverse docking was employed to identify putative targets for plant-derived proceraside A, frugoside, calotropin, and glycopentalone compounds, which demonstrated antiproliferative activity in several cancer cell lines. − In these studies, the ATPase domain of TopoII cocrystallized with an ANP ligand (PDB 1ZXM) was utilized among six other structures of proteins known to play critical role in cell proliferation, cell growth and DNA repair/replication. As the result, proceraside A molecule produced a docking score (software used AutoDock 4.2) comparable to the native ANP ligand and was proposed as a potential TopoII catalytic inhibitor.…”

“…Using reverse docking, researchers pinpointed TopoII as a potential target of several molecules with antiproliferative potential. 112,113,115 By comparing docking scores derived from different TopoII drug pockets, binding modes and molecular mechanisms of action of several compounds were elucidated. 124,126,129,131 Ligand−protein interactions of several TopoII inhibitors were explored with various computational tools.…”

Importance and Application of Computational Studies in Finding New Active Quinazoline Derivatives

“…Reverse pharmacophore mapping, for example, pharmacophore model of proteins in the list of targets, is the starting point for the comparison of the pharmacophore models with the studied ligand [23]. A freely accessible web server known as PharmMapper is considered as a valuable resource of pharmacophorebased reverse screening [25]. It attempts to find the potential target applicants for small-molecule drugs, natural compounds, or novel compounds whose targets are still unidentified [26,27].…”