In mitosis, microtubule dynamics ensure the successful capture, alignment, and segregation of chromosomes into the daughter cells.
Stabilizing or destabilizing microtubules in mitosis leads to mitotic arrest mediated by activation of the spindle-assembly checkpoint, and, in many cases, apoptotic cell death.
Our study demonstrates that SERMs can modulate microtubule assembly as a potential drug repurposing strategy for cancer treatment and suggests a hormone-independent mechanism for inhibiting cell proliferation.
We performed a structure-based comparison using the Pocket Feature algorithm to assess the similarity between the taxane pocket of beta-tubulin and the co-crystal structures retrieved from PDB (Fig. For a given residue in the binding site, the geometric center of the residues was determined based on the location of the heavy atom and a 6 Å microenvironment consisting of 6-concentric radial shells of 480 physical and biochemical descriptors was evaluated around each residue locus.
Therefore, identifying a generation of synthetic taxanes remains an attractive strategy for improving the current state of cancer treatment, especially if molecules with optimal pharmacokinetic properties and resistance profiles could be developed rapidly.
A promising strategy for anticancer drug discovery is drug repurposing, also known as drug repositioning, in which a known drug can be repurposed to address cancer indications based on previously off-target interactions.Target enrichment analysis showed that among the 36 ligands, the most abundant protein target families with sites similar to the taxane pocket were ERs (12), beta-tubulins (4), MAPK14 kinases (4), dihydroorotate dehydrogenases (DHODHs) (3), and 13 other proteins (Fig. The 12 ER ligands identified from our binding site similarity screen were predominantly SERMs, which are partial agonists of the ERs (Supplementary Data 2).Several SERMs are analogues of raloxifene (RAL) and tamoxifen (TAM), which are FDA-approved drugs for the treatment and prevention of osteoporosis, and for the reduction of breast cancer risk in postmenopausal woman.Other SERMs identified include 7-oxabicyclo[2.2.1]hep-2-ene sulfonate (OBHS) and tetrahydroisoquinoline phenols (THIQP) analogues.Ligand structure alignment based on protein microenvironments revealed consensus chemical features between paclitaxel and the predicted SERMs.a The computational workflow of identifying and validating ligands binding to the taxane pocket of microtubules.Microenvironments of the taxane pocket were compared to a database of protein pocket microenvironments bound to small molecule ligands.Microtubules transport and position cellular components in interphase and form the mitotic spindle in mitosis.Microtubule arrays in both cases are highly dynamic, with the assembly and disassembly of the polymer regulated by the intrinsic tubulin GTP hydrolysis and microtubule-associated proteins.Although widely used in the treatment of breast cancer and other malignancies, existing taxane-based therapies including paclitaxel and the second-generation docetaxel are currently limited by severe adverse effects and dose-limiting toxicity.To discover taxane site modulators, we employ a computational binding site similarity screen of 14,000 drug-like pockets from PDB, revealing an unexpected similarity between the estrogen receptor and the beta-tubulin taxane binding pocket.