Taxanes are a family of natural products with a broad spectrum of anticancer activity.This activity is mediated by interaction with the taxane site of beta-tubulin, leading to microtubule stabilization and cell death.For example, the two hydroxyl phenyl rings of SERMs and paclitaxel were found in a similar position.
Although paclitaxel and the second-generation docetaxel (Taxotere, Aventis, Bridgewater, NJ) are two of the most successful chemotherapies for the treatment of breast, ovarian, lung carcinomas, and other malignancies, their clinical use is hampered by drug resistance, hypersensitivity reaction to the drug vehicle, dose-limiting toxicity associated with neurotoxicity, myelosuppression, and other severe side effects.
Furthermore, most taxane drugs, both semisynthetic analogues of paclitaxel and natural products, have higher molecular weight than paclitaxel, are impractical for oral administration, and offer no improvement in clinical performance over the original compounds.
To quantify the binding site similarity, shared microenvironments between two protein-ligand pockets were used to determine a Pocket Feature Score (PFS), which indicates the likelihood that the ligand from the screened protein pockets will interact with the taxane site.
In silico binding site similarity screen identifies tubulin-ER cross-reactivity.
Evaluation of nine selective estrogen receptor modulators (SERMs) via cellular and biochemical assays confirms taxane site interaction, microtubule stabilization, and cell proliferation inhibition.
Our study demonstrates that SERMs can modulate microtubule assembly and raises the possibility of an estrogen receptor-independent mechanism for inhibiting cell proliferation..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.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.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.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.The recent wide availability of protein crystal structures from the protein data bank (PDB) offers potential opportunities to discover biological activities of known drugs based on detailed structural knowledge of the protein-ligand interaction.Here, we use a structure-based drug repurposing strategy to discover taxane site modulators by evaluating the similarity between the beta-tubulin taxane site and pockets of drug-like compounds.