Application of ensemble pharmacophore-based virtual screening to the discovery of novel antimitotic tubulin inhibitors

Abstract

Graphical abstract

A novel tubulin inhibitor, 6h, suppresses tumor-associated angiogenesis and shows potent antitumor activity against non–small cell lung cancers

“…, combretastatin A4), and insufficient potency ( e.g. , verubulin), colchicine-binding site agents have not been approved for cancer therapy so far ( 12 ). Thus, developing novel, safe, and highly efficacious colchicine-binding site agents to treat NSCLC is of paramount urgency.…”

Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells

“…Molecular docking studies predict the PILA9 binds to the colchicine site of tubulin, which likely underlies the microtubule alterations observed after treatment with this compound. The binding mode of PILA9 to the colchicine site of tubulin is like those of the MDS and to the experimentally determined binding modes of other colchicine site ligands such as the combretastatin A4 or colchicine [ 9 ], thus suggesting a common mechanism of action mediated by tubulin binding.…”

“…The carbonyl group of the carbamoyl group hydrogen bonds to the backbone NH of Val181α, in a similar way as the hydroxyl group of combretastatin A4 or the ketone of the tropolone of colchicine, while the amino group hydrogen bonds to the backbone carbonyl of Asn349β. The similar binding modes to the colchicine site of tubulin of PILA9 , the MDS, and combretastatin A4 or colchicine [ 9 ] suggest a common mechanism of action mediated by tubulin binding.…”

“…Ensemble docking studies to take into account the protein flexibility were carried out with 81 models of complexes of tubulin with structurally diverse colchicine site ligands as previously described [ 9 ]. Briefly, dockings for each ligand were run in parallel with AutoDock 4.2 [ 58 ] applying a grid spacing of 0.375 Å and a Lamarckian genetic algorithm (LGA) for a maximum of 2.5 × 10 6 energy evaluations 100–300 times, 150 individuals, and a maximum of 27,000 generations and with PLANTS [ 59 ] using the chemplp scoring function and a search speed of 1 with default settings and 10 runs.…”

“…These compounds can be divided into two main groups: microtubule-destabilizing agents and microtubule-stabilizing agents. Microtubule-destabilizing agents (MDA) inhibit microtubule polymerization and include several compounds such as the Vinca alkaloids, colchicine, or combretastatins [ 9 ]. On the other hand, microtubule-stabilizing agents inhibit microtubule depolymerization, and its main representative family is taxanes [ 8 ].…”